CN108642129A

CN108642129A - The medical usage of impulsion control disorder biological detection marker and Impulsins

Info

Publication number: CN108642129A
Application number: CN201810416580.0A
Authority: CN
Inventors: 刘俊平
Original assignee: Hangzhou Dui Li Biotechnology Co Ltd
Current assignee: Hangzhou Dui Li Biotechnology Co Ltd
Priority date: 2018-05-03
Filing date: 2018-05-03
Publication date: 2018-10-12
Also published as: WO2019210764A1; CN111455019A

Abstract

Invention provides a kind of medical usage of impulsion control disorder biological detection marker and Impulsins, it is applications of the ATP enzyme ATP13A2 in preparation behavior and dyskinesia disease organism detection marker, the behavior and dyskinesia are caused by nerve impulse control disorder and dyskinesia, and the amino acid sequence of ATP13A2 is as shown in SEQ.No.1.The present invention also provides ATP enzyme ATP13A2, and blood sphingomyelin to be caused to reduce the application with ceramide raising in preparing impulsion controlling behavior and dyskinesia disease organism detection marker extremely.The present invention also provides ceramides to apply similar to compound FTY720 or sphingomyelinase inhibiting compound Fluoxetine in preparing the drug for treating impulsion controlling behavior and dyskinesia disease.The present invention provides new medicine for behavior and dyskinesia disease.And it provides fundamental basis for clinical research behavior and dyskinesia disease.

Description

The medical usage of impulsion control disorder biological detection marker and Impulsins

Technical field

The invention belongs to biotechnology, it is related to a kind of marker more particularly to a kind of detection ATP enzyme ATP13A2 gene mutations, sheath Fat causes nerve impulse control, behavior and dyskinesia, and a kind of tool medicativeization for being referred to as Impulsins extremely Object, Impulsin-F1 (FTY720) or impulsin-F2 (Fluoxetine) are closed to the extremely relevant impulsion control barrier of sphingolipid Hinder aspect that there is medical usage, and in particular to FTY720 prevents nerve impulse control disorder（impulse control disorder, ICD）Impulsion is controlled with the medical usage more particularly to FTY720 of locomotor ataxia, paralysis and dementia Parkinson's disease in disorderly and neurodegenerative disease（Parkinson disease, PD）, spastic paralysi, neuron The medical usage of ceroid lipofuscinosis and Kufor-Rakeb dementias.

Background technology

Movement and behavior disorder, cause very big harm to patient, family and society, are facing caused by neurodegenerative disease Lack the therapy of radical cure on bed always.Include Parkinson's disease with dyskinesia caused by the relevant neurodegenerative disease of aging （Parkinson disease, PD）, Kufor-Rakeb dementias, hereditary spastic paraplegia (spastic Paraplegia, SPG) and neuron control systems (neuronal ceroid lipofuscinosis, NCL).Incidence of the Parkinson's disease in China is slightly above western countries, and the incidence of over-65s old man is 1.7%, is the whole world The most country of parkinsonian's quantity.Numerous studies show whether static tremor or myotonia, movement late Slow and gait disorder dyskinesia, all with substantia nigra of midbrain dopamine（dopamine, DA）Serotonergic neuron senescense and damnification is related. The gradual senescense and damnification that specific brain area domain occurs causes occur eosinophilic inclusion in neuron（Lewy body）, lead to god It is lost through meta function, therefore denaturation and death, striatum DA level also substantially reduce.It is treated although dopaminergic nerve medium substitutes Method can cause part to be alleviated, but can also cause include serious behavior disorder side effect.The behavior disorder of parkinsonian It often shows as such as frequently seeking a spouse and the excessive not autonomous impulse control disorder of mating behavior, and its pathogenesis is unknown always, Clinically it is referred to as impulsion control disorder.

Impulsion control disorder（Impulse control disorder, ICD）Itself it is clinically relatively conventional behavior It is abnormal, it accounts for the 3% of adult, usually fallen ill earlier in the young stage, but in parkinsonian in apparent phenomenon occurred frequently （25-50%）, during especially frequently appearing in dopamine replacement therapy, very big pain is brought to patient and relatives.Clinic is examined Disconnected to rely primarily on interrogation assessment, not no effective and immunotherapy targeted autoantibody is urgent problem to be solved for a long time.The impulsion of behavior Control is an important mechanisms of people and animal physiological behavioural norm, is the result of social animal survival evolution.Several centuries with Come, people worry always and do not understand the abnormal behaviour that impulsion control occurs why in terms of behavior.Although impulsion control is abnormal It is common in young people, but also occur in adult and even accompany throughout one's life, that is, control disorder of getting excited（impulse control disorder, ICD）.Its behavior includes excessive diet and excessively combs skin injury (trichotillomania, TTM) etc.. Parkinsonian often simultaneously tool there are two types of or more the not normal symptom of impulsion control, be most commonly that sexual function is high in male Into, and the common TTM self-inflicted injuries nail of female patient or skin（Skin pick, SP).

The pathologic basis of impulsion control disorder patient may arrive corpus straitum circuit functionality with Prefrontal Cortex supraoptic region (OFC) Obstacle is related.The imaging of parkinsonian's nerves within the body also shows the areas YouOFCFu dysfunction, including OFC is controlled from top to bottom Miopragia or brain processed bottom includes corpus straitum limbic system " ventrolimbic " hyperactivity, leads to signal of excessively getting excited. OFC, serotonin（5-HT）The inhibition that reducing makes brain generate impulsion for reward weakens.This inhibiting effect（Referred to as reversal learning）It is a mechanism of behavior flexibility, it relies on the integrity function of OFC- corpus straitum loops.Have Research report, can induce impulsion control disorder during treating Parkinson's disease using treatment in dopamine.Show that limbic system is more Bar amine receptor activity increases, such as dopamine D 3 receptor activity may participate in mediating impulsion control disorder, but also have research to point out simultaneously It is far from it.Also some researches show that glutamates may be disorderly in impulsion control with cingulate gyrus and OFC by connecting amygdaloid nucleus hypothalamus Disorderly participate in ICD, TTM, SP and anxiety process.Therefore, 5-HT receptor actives and the adjusting reward that cognition flexibility ratio is adjusted in OFC are strong Change behavior, the connection areas corpus straitum Fu He and the dopamine in cingulate gyrus abdomen proparea and the balance of cns glutamate activity are impulsion regulation and control The component part of physiological mechanism.Currently, it is related the related Parkinson's disease of impulsion control disorder occur to parkinsonian Gene is not verified also.

Lysosome is 0.1-1.2 microns of film property organelle, is operated by cross-film and is melted with other subcellular structures It closes, lysosome is by the way that from cellular uptake or pinocytosis from extracellular intake, matter is executed to cytoplasm and organelle homeostasis Amount control, adjusts cell micro-environment stable state.Research shows that lysosome membrane operating obstacle and quantity are reduced and Parkinson's disease DOPA Amine neuron denaturation is related.Lyase bulk damage causes lysosome to hoard disorder（LSD）, certain lysosomes hoard disorders, such as Gaucher disease（Gaucher disease, GD）, Niemann-Pick disease（NPC）It is identical as the molecular pathology of Parkinson's disease, packet Include Lewy body eosinophilic inclusion.It is reported that lysosome SMPD1 and NPC1 gene mutation may be Parkinson's disease Risks and assumptions.Therefore, lysosome molecule operating and metabolism may directly affect structure of the alpha-synapse nucleoprotein in neuron and Solubility, lysosomal dysfunction may then promote formation and the neuron senescence denaturation of Lewy body eosinophilic inclusion.

ATP13A2（P-type ATP enzyme）Gene is the pa gold for being located at No. 1 sites chromosome 1p36 recessive inheritance person between twenty and fifty morbidity Sen Shi disease Disease-causing genes, coding 1180 amino acid, containing 10 times it is hydrophobic（Cross-film）Area.As the 5th class of p-type ATP enzyme family（P- type ATPase group 5）, ATP13A2 plays a significant role in adjusting lysosome stable state.In young op parkinson's sufferer In person, it has been found that a variety ofATP13A2Gene mutation.It is found in original cuiture neurons of rats, the ATP13A2 of wild type can be protected It protects cell and to the toxic effect of cell and reduces the release of mitochondrial cytochrome c from manganese ion, and its pathogenic mutation body is then Without this ability, illustrate that ATP13A2 protects cells from the cytotoxicity of manganese ion by adjusting the stable state of cell manganese ion.Research It was found that interfering the generation that the expression of ATP13A2 leads to a large amount of ROS, Jin Eryin in the neuron and cerebral cortical neuron of culture Hair line mitochondria function is abnormal.ATP13A2 is not yet determined as lysosome cross-film ATP enzyme, corresponding specific substrate ligand.It lacks There is the aggregation of gliomatosis ubiquitin protein, lipofuscinosis, cell endocytic approach obstacle in the mouse of weary ATP13A2 And the dyskinesia of age-related similar Parkinson's disease.ATP13A2 gene mutation Parkinson's diseases are with wide Lyase bulk damage, including the processing of lysosomal acidification, hydrolase and degradation of substrates dysfunction, autophagosome, which is removed, to be reduced, and α-is prominent Touch nucleoprotein aggregation and cell death.

Invention content

The object of the present invention is to provide a kind of applications of ATP enzyme ATP13A2 in the marker of the behavior of preparation and dyskinesia, institutes It is caused by nerve impulse control disorder and dyskinesia to state behavior and dyskinesia, and the nerve impulse control disorder and movement hinder Hinder because ATP enzyme ATP13A2 mutation cause serum sphingomyelin to reduce and ceramide increases, the gene order of the ATP13A2 With protein sequence as shown in SEQ. No. 1-2.

Impulsion control disorder biological detection marker provided by the invention, i.e., lysosomal membrane protein53 ATP enzyme in cell ATP13A2 mutation, serum sphingomyelin reduce and ceramide increases more particularly to Parkinson's disease is with impulsion control disorder Behavior and dyskinesia biological detection marker（Fig. 1-6）.

The second object of the present invention is to provide application of a kind of compound in the drug of preparation behavior and dyskinesia.Especially It is to prepare Parkinson's disease with impulsion control disorder, the drug of behavior and dyskinesia.The compound is FTY720 and Fluoxetine.

The present invention provides FTY720 and is applied in treatment behavior and dyskinesia drug, is especially preparing not only to pa gold The impulsion control disorder of Sen Shi diseases is effective, also in the dyskinesia active drug of the neurodegenerative diseases such as Parkinson's disease Application.Neurodegenerative disease includes Kufor-Rakeb dementias, hereditary spastic paraplegia (SPG) and neuron wax Sample matter lipofuscinosis (NCL).FTY720 or Fingolimod, molecular formula C₁₉H₃₃NO₂.HCl, chemical name 2- Amino-2- [2- (4-octylphenyl)] -1,3-propanediol hydrochloride, molecular weight 343.94g/ mol。

It is reduced with sphingomyelins in view of the mouse impulse control disorder observed and ceramide increases, we have screened punching The inhibiting factor of dynamic control obstacle（Impulsivity inhibitors, or be Impulsins）.We have found two changes Closing object has the activity of Impulsin, and one is Impulsin-F1, is the compound FTY720 of known similar ceramide. Another Impulsin-F2 has the compound Fluoxetine for inhibiting sphingomyelinase to be known.FTY720 or Fingolimod（Molecular formula is C₁₉H₃₃NO₂.HCl, chemical name is 2-amino-2- [2- (4-octylphenyl)] -1,3- Propanediol hydrochloride, molecular weight 343.94g/mol）Once by as the immune of inhibition lymphocyte function Inhibitor is inhibiting organ transplantation reaction to ratify clinical treatment because certainly in FDA in the U.S. as a line drug candidate Multiple sclerosis caused by body is immune, is not found acute and chronic neurotoxicity, gene mutation, is broken and energy is caused to fail Effect.During we screen Impulsins, Normal group and ATP13A2 gene knockout group mouse are given FTY720 (Impulsin-F1) is injected intraperitoneally, FTY720（5 mg/kg/day）, after 1 week once a day, FTY720 is to normal small Mouse does not have obvious toxic-side effects, but then has obvious inhibiting effect to the behavior and dyskinesia of ATP13A2 shortage mouse（Figure 7）.ATP13A2 mouse after the medicine completely inhibit the excessive mating behavior of animal（Fig. 7 A）, excessively comb behavior（Fig. 7 B）, complete The full motor coordination function of restoring mouse（Fig. 7 C）.Therefore, FTY720 has the work for the treatment of impulse control disorder and dyskinesia With curative effect understands, the complete feature of therapeutic effect, is locomotor ataxia, paralysis and the impulsion control disorder of Parkinson's disease sample Individual provides current only treatment means and method.

The present invention provides applications of the Fluoxetine in preparing treatment behavior and dyskinesia drug, is especially preparing It is not only effective to the impulsion control disorder of Parkinson's disease, the dyskinesia also to neurodegenerative diseases such as Parkinson's diseases Application in effective drug, the neurodegenerative disease includes Kufor-Rakeb dementias, hereditary spastic paraplegia (SPG) and neuron control systems (NCL).Fluoxetine or Prozac, also referred to as Prozac, chemistry Molecular formula is C₁₇H₁₈F₃NO.HCl, molecular weight 345.79 are that a kind of approval is clinically used for antidepression, obsessive-compulsive disorder, fear etc. The drug of symptom.During we screen Impulsins, Normal group and ATP13A2 gene knockout group mouse are given Fluoxetine (Impulsin-F2) is oral, Fluoxetine in reference wet suit with after (20 mg/kg/d) 1 week, Fluoxetine lacks the behavior of mouse and dyskinesia to ATP13A2 then has obvious inhibiting effect（Fig. 8 A-D）.After the medicine ATP13A2 mouse completely inhibit animal and excessively comb behavior（Fig. 8 A-B）With excessive mating behavior（Fig. 8 C-D）.Therefore, Fluoxetine understands impulsion control disorder with curative effect, is administered orally and facilitates feature.

（1）We have discovered that ATP13A2 shortages cause excessively combing, epilation and skin autotomy.By establishing ATP13A2 knock out mice,ATP13A2LoxP gene locis are inserted into the 2-3 exons both sides of gene, genotype identification with Gene expression analysis confirms the knockout of ATP13A2（Figure 1A-D）.By observing ATP13A2 knock out mice, Wo Menfa Existing ATP13A2 lacks mouse when 3-4 months big, has and significantly excessively combs hair, excessively tears hair and hold in the month and peck skin The phenomenon that（Fig. 2A-G）.These mouse the body surface of back, neck, eyebrow, beard, cheek, head or chest occur bald spot or Skin wound（Fig. 2A）.Mouse habit tracking picture-recording shows that ATP13A2 knock-out mices take more compared to wild-type mice Self reason hair/hair that more times carry out repeatability in a certain position of its body surface is pullled, the attack times and input of grooming The average value of time can reach three times of wild type control group mouse, and female ATP13A2 knock-out mices hair, which tears and holds in the month, to be pecked The case where skin, is compared to male ATP13A2 knock-out mices incidence higher（Fig. 2 B）.ATP13A2 knock-out mice hairs tear with It holds the case where pecking skin in the month, is obviously increased on daytime and the number of evening breaking-out and time（Fig. 2 B-D）, while with excessive coke Consider and frightened（Fig. 2 E）.The stress stimulation that circadian rhythm changes obviously aggravates excessively to comb behavior（Fig. 2 F）.Serious ATP13A2 The autotomy that knock-out mice is shown causes epidermis to fray, bleeding, subcutaneous and muscle damage damaged skin feature（Fig. 2 G）, With clinic epilation disease（TTM）And the symptom of scratch disease patient is similar.

(2) ATP13A2 shortages cause the hyperfunction, same sex mating behavior of male mouse mating.For male ATP13A2 knock-out mices, Then show apparent excessive mating behavior（Fig. 3）.Especially 3-6 monthly ages ATP13A2 knock out mice chase, hear smell, Mating is crouched down wild type female mice and is obviously increased（Fig. 3 A-C）, and occur at any time section, do not distinguish round the clock（Fig. 3 D）. ATP13A2, which lacks male mouse and is inserted into and ejaculates the time in mating, to be obviously prolonged, and first time mate before the dormancy phase then shorten （Fig. 3 E-F）.Lack the effect to behavior for the ATP13A2 of clear nerve-specific, We conducted the adjustings of Nestin promoters The nerve-specific ATP13A2 conditionitys that cre is mediated knock out（CKO）, neuronal specificity knockout ATP13A2 hero mouse are for female Mouse chases and attempts to mate and hear the behavior smelt to male mice genitals to be remarkably reinforced, and this behavior can be continued until Mouse Age reaches 12 months（Fig. 3 G-H）.In addition, the male that ATP13A2 is knocked out is in the life of living together with all ages and classes female mice In work, these ATP13A2 lack mouse and attempt to mate with the female mice of all month age brackets from 3 to 12, not table Reveal any preference, compared with wild-type mice, 3-6 times of number of copulations average out to（Fig. 3 I）.By the way that ATP13A2 is knocked out male Mouse mates with same strain male mice, it is observed that ATP13A2 knocks out reproduction of the male mice to another male mice Organ news is smelt（Fig. 3 J are left）And mating（Fig. 3 J are right）It is obviously higher by control, ATP13A2 knocks out what male mouse mated to same sex mouse Behavior increases by 4 times（Fig. 3 J are right）.The male mice that ATP13A2 is knocked out is to the reproductive organs taste preference of same sex mouse also than wild Type mouse is significantly raised（Fig. 3 K）.As it can be seen that ATP13A2 heros mouse significantly mates, hyperfunction behavior is not only to all ages and classes female mice without choosing It selects（Fig. 3 I）, and the frequent behavior that mates with same sex hero mouse（Fig. 3 J-K）.

（3）ATP13A2 shortages cause to increase age dependence dyskinesia.It excessively combs, pull off the feather of caused by ATP13A2 shortages, certainly Residual skin and the impulsion control excessively to mate are abnormal, and dyskinesia is developed into after the age reaches 12 months.Such as Fig. 4 institutes Show, 12 monthly age ATP13A2 knock-out mices are dyskinesia from impulsion control Abnormal Development, and specific manifestation includes that ATP13A2 is knocked out There is limbs relaxation obstacle in mouse（Fig. 4 A）, show small gait walking movement（Fig. 4 B）.Turn-club test shows, the 3-6 monthly ages ATP13A2, which lacks mouse, motor coordination obstacle（Fig. 4 C）.Neuronal specificity knocks out ATP13A2 and equally causes the not same month Age mouse movement asynchronism（Fig. 4 D）.Compared with wild-type mice, the hind leg toe wedge angle degree of ATP13A2 knock-out mices（FBA） It is obviously reduced（Fig. 4 E-F）.ATP13A2 knock-out mice hind leg standing behaviors significantly reduce, than the hind leg station of wildness control mice Vertical number reduces 80%（Fig. 4 G）.Illustrate that ATP13A2 missings result in and clinical Parkinson's disease, spastic paralysi and NCL Spastic paraplegia is similar with ataxic gait defect in illness.

Lipodogramme group credit analysis is carried out by lacking mouse to ATP13A2, it has been found that ATP13A2 is that sphingolipid stable state must It needs.Sphingolipid includes sphingomyelins（Sphingomyelin, SM）, ceramide（Ceramide, Cer）And sphingol （Sphingosine, Sph）.Its sphingomyelin accounts for sphingolipid 80%, is the main phospholipid in cell membrane, to forming and maintaining cell Film asymmetry structure, Lipid Rafts (Lipid rafts), cell transport and communication function, all play an important role¹⁵.But work as When ATP13A2 lacks, mice serum sphingomyelin compares wild type control group and significantly reduces（Fig. 5 A）, and ceramide, 16 and 18 carbon fatty acids and lysosome phosphatidyl-ethanolamine then obviously increase (Fig. 5 B, 6A-B).And in contrast, ATP13A2 lacks small Lysosome phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidylinositols do not show significant change in mouse serum（Fig. 5 C-D, 6C- D）.Therefore, sphingolipid characteristic changes in ATP13A2 mutation, blood, and especially sphingomyelins lacks and ceramide increases, with impulsion Controlling behavior and dyskinesia are related.

The present invention provides a kind of biomarker of detection impulsion control disorder, i.e. ATP13A2 is abnormal, blood sphingomyelins reduces It is increased with ceramide；The present invention also provides a kind of ceramide similar to compound FTY720 in impulsion control disorder and/or fortune Dynamic disorder remedies are applied in preparing, and a kind of sphingomyelinase inhibiting compound Fluoxetine of offer is in impulsion control disorder medicine Object is applied in preparing.The present invention is clinical treatment causes behavior impulsion control disorder to carry because sphingomyelins lacks and ceramide increases For new medicine.

Description of the drawings

Fig. 1 is to detect ATP13A2 knock out mice allele and gene table in one embodiment of the invention Up to data.A：Using the DNA probe for non-targeted gene region show the normal ATP13A2 of control-animal gene size and The truncation ATP13A2 genes of knock-out animal.B、C:Using for external source Neo DNA（B）With the sources Inner gene order probe in detecting base Because knocking out result.D:Genotyping shows that ATP13A2 knock-out mices lack 2-3 exons.E:Using reverse transcription PCR method Detect ATP13A2 mRNA level in-sites in mouse brain and liver organization.F：It is different with western blotting method detection brain using RT-PCR Region ATP13A2 gene expressions and protein content level.

Fig. 2 be in one embodiment of the invention detection ATP13A2 lack mouse skin fixed area epilation and The impulsion for damaging skin controls abnormal behaviour.A：The picture A TP13A2 of regiospecificity depilation lacks mouse photo.B：Age exists The mouse epilation incidence of the 3-4 months.Mean value, standard error and p value are the observation results of every group of 50 animals.C-D：6 monthly age mouse are combed Reason and epilation attack times (C) and time (D).* show p<0.05, * * shows p<0.01, * * * show p<0.001, every group dynamic Object quantity=12.E：Distance, time and the frequency for entering central area that 6 monthly age female mices move in spacious field, n=16-17.F：Pass through Change circadian rhythm stimulation oversaturation and combs duration of seizure.Every group of size of animal=10.G：Excessive epilation and autotomy leads to serious skin The photo of skin damage.

Fig. 3 be in one embodiment of the invention detection ATP13A2 shortage cause male mouse erotopathy it is hyperfunction, mating Disorderly data.A：Different Month ATP13A2 hero mouse chase female mice frequency.By by the male mouse being housed individually with it is ready wild Type female mice is lived together, video observation is lived together start after in 25 minutes male mouse chase the time number of female mice, n=24.B：ATP13A2 is lacked Weary male mice hears the frequency for smelling female mice mouse propagation device, the C of n=24.：Different Month ATP13A2 lacks mouse mating and crouches down open country The frequency of raw type female mice, n=24.D：ATP13A2 lacks mouse mating and crouches down（It is left）And ejaculation（It is right）Time, n=17.E： ATP13A2 shortage mouse mate round the clock crouches down frequency, n=10.F：From the incubation period for mating mating for the first time, n=24.G：Nerve Particular conditions knock out（CKO）For the first time mating incubation period of the ATP13A2 mouse to female mice（n-10）And hunting frequency（n=11）.H： All ages and classes ATP13A2 CKO mouse smell frequency, n=16 to female mice genitals news.I：ATP13A2 lacks male mouse to Different Month Frequency, n=10 are crouched down in female mice mating.J：Male mouse smells male mouse sexual organ news（It is left）It is crouched down with mating（It is right）Frequency, n=10.K： ATP13A2 lacks reproduction smell preference of the mouse between male and female mouse.The genitals being applied on slide are divided by mouse Secretion news is smelt, and record contacts the time number of secretion on slide, n=10 with mouth and nose in 3 minutes.

Fig. 4 is that detection ATP13A2 lacks the data for causing dyskinesia in one embodiment of the invention.A：Limbs Contracture, the Radiologic imaging for loosening obstacle.B：Abnormal gait and the paces length shortened.Upper figure is the quantitative survey of length of marking time Amount, figure below are representative mouse footprint.C：The coordination ability is damaged.Mouse is placed on above a rotating rod, rotating rod with Friction speed rotates（3-6 20 turns per minute of month old mices, 12-18 15 revs/min of monthly age, 24 5 revs/min of monthly ages）, every time Animal stays in the time on rotating rod to detection record three times.Every group of animal 15.D：Nerve-specific condition knocks out ATP13A2 pairs Influence of the mouse in transfer rod movement（20 revs/min）, n=15.E：24 monthly age ATP13A2 knock out mice walking disorders occur Strephexopodia picture, the angle for the foot and basis that display is formed by toe position（Foot-base angle, FBA) it is different（It is wild Animal blue line, ATP13A2 knock out red line）.F：ATP13A2 lacks mouse FBA detections, n=4-9.G：All ages and classes ATP13A2 bases Because of the standing checking experiment of knock-out mice, n=5.

Fig. 5-6 is that detection ATP13A2 lacks iipidomic variation in mice serum in one embodiment of the invention, Data display lacks ATP13A2 and mouse sphingomyelins is caused to reduce, and ceramide increases.Wild type and ATP13A2 knock-out mices Each four 50 microlitres of serum are used for methanol（500 microlitres）It is extracted respectively with chloroform, 1：1 butanol/methanol（BuOH/MeOH）It is outstanding Liquid chromatography mass spectrometric combination is carried out after floating lipid（LC/MS）Analysis.5A：Sphingomyelins, 5B：Ceramide, 5C：Lysosome phosphatidyl courage Alkali, 5D：Phosphatidyl choline, 6A：Aliphatic acid, 6B：Lysosome phosphatidyl-ethanolamine, 6C：Phosphatidyl-ethanolamine, 6D：Phosphatidyl-4 Alcohol.Asterisk (*):Haggle over wild type control, p<0.05.

Fig. 7-8 is that detection FTY720 (Impulsin-F1) lacks ATP13A2 in one embodiment of the invention Cause the function and effect of mouse behavior and dyskinesia.3-6 monthly ages wild type and ATP13A2 knock out mice are receiving physiology After salt water injection one week, observed behavior and movement phenotype, receiving FTY720, (Impulsin-F1,5mg/kg/day, 50 are micro- Rise) it is injected intraperitoneally one week, it then records and is to the effect of behavior and movement after comparing FTY720 (Impulsin-F1) injections No relatively physiological saline has different-effect.7A：FTY720 (Impulsin-F1) lacks mouse mating row to male ATP13A2 For effect.7B：FTY720 (Impulsin-F1) lacks female ATP13A2 the effect that mouse combs behavior.7C：FTY720 (Impulsin-F1) lack the effect of the transfer rod motor behavior of mouse to ATP13A2.Asterisk (*): p<0.05.8A-D: Fluoxetine (Impulsin-F2) does not have obvious toxic-side effects to normal mouse, but lacks the behavior of mouse to ATP13A2 It is abnormal then have apparent suppression therapy effect.Fuoxetine（Impulsin-F2,20mg/kg/ days）Oral medication after a week, The excessive combing behavior that ATP13A2 lacks animal is obviously corrected（8A-B）, the excessive mating behavior of animal obviously corrected （8C-D）.

Specific implementation mode

Embodiment of the present invention is described in detail with example below in conjunction with the accompanying drawings, implementation example is merely to illustrate this Invention, without taking an entrance examination as restriction the scope of the present invention.The person that is not specified actual conditions in embodiment, according to normal condition or manufacturer It is recommended that condition carry out, agents useful for same or instrument, which are not specified, generates manufacturer person, and being can be with conventional products that are commercially available.

1 ATP13A2 of embodiment mutation and/or serum sphingomyelin reduction, ceramide and lysosome phosphatidyl-ethanolamine Increase, be the biomarker of anxiety and behavior, dyskinesia, impulsion control disorder, the Parkinson such as especially pull off the feather of, take off skin Family name's disease, Kufor-Rakeb dementias, hereditary spastic paraplegia (SPG) and neuron control systems (NCL) Marker：

Experimental subjects：Wild type and ATP13A2 gene mutation C57BL/6 experiment mices

Experimental method：Whole body or neuronal specificity expression cre recombinase-mediateds gene knockout, behaviouristics and serum lipids group It learns.Being generated from mouse 129Sv/J genomic dna sequences by PCR has both ends homologous recombination and LoxP-Exon 2- 3-FRT- Neo Cassette-FRT-LoxP of Exon and both ends are used for the DNA fragmentation of homologous recombination, this carrier is led to The 28 generation embryos for crossing the W9.5 that electrotransfection insertion is obtained from 60 mouse of 1291/Sv-p+Tyr+KitlSl-J/+ are dry（ES）Cell In, separation tool there are two the targeting W9.5 ES cells in the sites loxP and is injected into C57BL/6 blastaeas after homologous recombination, is generated ES cytochimeras with W9.5 donors and C57BL/6 receptors generate chimera C57BL/6 mouse by breeding and obtain heredity Modification transmitted through system genitale, by constantly mate with C57BL/6 mouse acquisition wt/floxP heterozygotes, and then with ROSA-26 Gene knockout heterozygote (wt/KO/cre) is realized in point Cre recombinases transgenic mice (C57BL/6-OzCRE) mating, is had dynamic The exon 2-3 and pkg-neo frames that object tail tissue genotype identification and gene expression detection prove knock out (Fig. 1).Animal Behaviouristics phenotype be to be observed by real-time recording, the statistics in different time stage and statistics comparative analysis obtain notable Sex differernce conclusion.

As a result it shows：ATP13A2 gene knockouts have not significant impact animal development, birth, growth and survival.But The forfeiture of ATP13A2 functions causes mouse excessively to be combed to fur generation impulse control disorder, generation, pull off the feather of, scratch the different of skin Normal impulsive action, is especially only just of age or low age jenny.It is special that these behavior specific manifestations are included in certain regional area Property combing repeatedly, drawing extract hair, lead to the hair missing in each comfortable different parts of mouse, such as face, eye circumference, preceding Volume, the crown, neck and back and abdomen etc.（Fig. 2A）.Abnormal behavior is higher than male mouse in female mice incidence, duration of seizure regardless of Round the clock or time phase（Fig. 2 B-D）, and have anxiety and frightened behavior simultaneously（Fig. 2 E）.Circadian rhythm changes stress stimulation and aggravates Behavioral seizures number and time（Fig. 2 F）, What is more then there is local skin and scratches, occur skin surface and it is subcutaneous it is damaged, go out The major injuries such as blood（Fig. 2 B, G）.Serologic detection shows that sphingomyelins reduces, and ceramide increases, lysosome phosphatidyl-ethanolamine Increase（Fig. 5-6）.

2 ATP13A2 of embodiment mutation and/or serum sphingomyelin reduction, ceramide and lysosome phosphatidyl-ethanolamine Increase, is the marker of the abnormal hyperfunction same sex mating that such as mates of mammal male impulsion control

Experimental subjects：Wild type and ATP13A2 gene mutation C57BL/6 experiment mices.

Experimental method：Whole body or neuronal specificity expression cre recombinase-mediateds gene knockout, behaviouristics and serum lipids Group learns detection.The behaviouristics phenotype of animal is observed by real-time recording, and the statistics and statistics in different time stage compare Analysis obtains significant difference conclusion.

As a result it shows：The forfeiture of ATP13A2 functions causes mouse mating impulse control disorder, frequent abnormal impulses and friendship occurs With behavior, especially it is only just of age or low age buck.Specific manifestation is that gene mutant animals are frequently chased, hear and smell, hand over by force With jenny（Fig. 3 A-C）, regardless of time section, do not distinguish round the clock（Fig. 3 D）, it is inserted into mating and the time of ejaculating obviously prolongs It is long, dormancy phase shortening before mating for the first time（Fig. 3 E-F）, female not of the same age is not selected（Fig. 3 I）.To same gender buck Also it seeks a spouse mating behavior（Fig. 3 J-K）.Serologic detection shows that sphingomyelins reduces, and ceramide increases, lysosome phosphatidyl Ethanol amine increases（Fig. 5-6）.

3 ATP13A2 of embodiment lacks or dysfunction, and/or serum sphingomyelin reduction, ceramide and lysosome Phosphatidyl-ethanolamine increases, and is the biomarker of mammals age and related neurodegenerative disease, especially op parkinson's Disease, Kufor-Rakeb dementias, hereditary spastic paraplegia (SPG) and neuron control systems (NCL) draw The marker of the Tongji University's imbalance, paralysis that rise:

As a result it shows：ATP13A2 functions lose the motor coordination dysfunction for causing mouse gradually to be aggravated with increasing age, paralysis Paralysis, especially advanced age animal.Specific manifestation is that gradual asynchronism, incoordination occur for gene mutant animals, is finally paralysed. It is embodied in limbs hypermyotonia, relaxation obstacle（Fig. 4 A）.It walks small gait, it is similar with Parkinson's disease（Fig. 4 B）. Rotate disequilibrium and grip on pole（Fig. 4 C-D）.Difficulty in walking, the strephexopodia, dysstasia（Fig. 4 E-G）.Serologic detection Show that sphingomyelins reduces, ceramide increases, and lysosome phosphatidyl-ethanolamine increases（Fig. 5-6）.

4 one kind compound Impulsins of embodiment is the treatment dyskinesia such as impulse control disorder and Parkinson's disease Effective ways：

Experimental method：Whole body or neuronal specificity expression cre recombinase-mediateds gene knockout are detected with behaviouristics.Divide before detection Be not injected intraperitoneally once a day FTY720 (Impulsin-F1,5mg/kg, 50 microlitres）.The chemical constitution of FTY720 is： 2-amino-2- [2- (4-octylphenyl)] -1,3-propanediol hydrochloride, molecular weight 343.94.Note Penetrate the change of the behavior and motor function that lack animal before comparing injection after a week and after injection to wild type and ATP13A2.It is dynamic The behaviouristics phenotype of object is observed by real-time recording, and the statistics in different time stage and statistics comparative analysis are shown Write sex differernce conclusion.

As a result it shows：FTY720 （Impulsin-F1）There is no obvious toxic-side effects to normal mouse, but ATP13A2 is lacked The behavior of weary mouse and dyskinesia then have apparent suppression therapy effect（Fig. 7）.With the medicine after one week treatment, ATP13A2 is lacked The weary excessive mating behavior of animal obtains global correction（Fig. 7 A）, the excessive combing behavior of animal also corrects completely（Fig. 7 B）, animal Motor coordination dysfunction also restored completely（Fig. 7 C）.

5 one kind compound Impulsins of embodiment is the treatment dyskinesia such as impulse control disorder and Parkinson's disease Effective ways：

Experimental method：Whole body or neuronal specificity expression cre recombinase-mediateds gene knockout are detected with behaviouristics.Divide before detection Fluoxetine (Impulsin-F2) Jin Hang not be taken orally daily（20mg/kg/ days）.The chemical constitution of Fluoxetine is： C₁₇H₁₈F₃NO.HCl, molecular weight 345.79.It takes orally after a week, is lacked before relatively taking orally and to wild type and ATP13A2 after taking orally The behavior of weary animal and the change of motor function.The behaviouristics phenotype of animal is observed by real-time recording, the different time stage Statistics and statistics comparative analysis obtain significant difference conclusion.

As a result it shows：Fluoxetine (Impulsin-F2) does not have obvious toxic-side effects to normal mouse, but right The abnormal behavior that ATP13A2 lacks mouse then has apparent suppression therapy effect（Fig. 8 A-D）.With the medicine after one week treatment, The excessive combing behavior that ATP13A2 lacks animal is obviously corrected（Fig. 8 A-B）, the excessive mating behavior of animal obviously entangled Just（Fig. 8 C-D）.

Sequence table

<110>The graceful Bioisystech Co., Ltd in Hangzhou

<120>The medical usage of impulsion control disorder biological detection marker and Impulsins

<160> 2

<170> SIPOSequenceListing 1.0

<210> 1

<211> 4061

<212> DNA

<213> Homo sapiens

<400> 1

agagggccgg gcggggcttg cggcgcgcac ggagggactg cggcagtgtc ggagccgcgc 60

cgagcctggt ggcccaggtg ccccgcccgc gtcagccctg ctccagcccc gcgctagccc 120

agcgcccctc gccccgggcc gtccggaccg cgcccccgcc cagggccttg cgcacgccgg 180

ggcccaggcc gagggccgca gcgccggggc cggcgatgag cgcgaggagc cggcatgagc 240

gcagacagca gccctctcgt gggcagcacg cccaccggtt atgggaccct gacgataggg 300

acatcaatag atcccctcag ctcctcagtt tcatccgtga ggctcagcgg ctactgtggc 360

agtccatgga gggtcatcgg ctatcacgtc gtggtctgga tgatggctgg gatccctttg 420

ctgctcttcc gttggaagcc cctgtggggg gtgcggctgc ggctccggcc ctgcaacctg 480

gcccacgccg aaacactcgt tatcgaaata agagacaaag aggatagttc ctggcagctc 540

ttcactgtcc aggtgcagac tgaggccatc ggcgagggca gcctggagcc gtccccacag 600

tcccaggcag aggatggccg gagccaggcg gcagttgggg cggtaccaga gggtgcctgg 660

aaggatacgg cccagctcca caagagcgag gaggcggtga gtgtcggaca gaagcgggtg 720

ctgcggtatt acctcttcca gggccagcgc tatatctgga tcgagaccca gcaagccttc 780

taccaggtca gcctcctgga ccatggccgc tcttgtgacg acgtccaccg ctcccgccat 840

ggcctcagcc tccaggacca aatggtgagg aaggccattt acggccccaa cgtgatcagc 900

ataccggtca agtcctaccc ccagctgctg gtggacgagg cactgaaccc ctactatggg 960

ttccaggcct tcagcatcgc gctgtggctg gctgaccact actactggta cgccctgtgc 1020

atcttcctca tttcctccat ctccatctgc ctgtcgctgt acaagaccag aaagcaaagc 1080

cagactctaa gggacatggt caagttgtcc atgcgggtgt gcgtgtgccg gccaggggga 1140

gaggaagagt gggtggactc cagtgagcta gtgcccggag actgcctggt gctgccccag 1200

gagggtgggc tgatgccctg tgatgccgcc ctggtggccg gcgagtgcat ggtgaatgag 1260

agctctctga caggagagag cattccagtg ctgaagacgg cactgccgga ggggctgggg 1320

ccctactgtg cagagacaca ccggcggcac acactcttct gcgggaccct catcttgcag 1380

gcccgggcct atgtgggacc gcacgtcctg gcagtggtga cccgcacagg gttctgcacg 1440

gcaaaagggg gcctggtgag ctccatcttg cacccccggc ccatcaactt caagttctat 1500

aaacacagca tgaagtttgt ggctgccctc tctgtcctgg ctctcctcgg caccatctac 1560

agcatcttca tcctctaccg aaaccgggtg cctctgaatg agattgtaat ccgggctctc 1620

gacctggtga ccgtggtggt gccacctgcc ctgcctgctg ccatgactgt gtgcacgctc 1680

tacgcccaga gccgactgcg gagacagggc attttctgca tccacccact gcgcatcaac 1740

ctggggggca agctgcagct ggtgtgtttc gacaagacgg gcaccctcac tgaggacggc 1800

ttagacgtga tgggggtggt gcccctgaag gggcaggcat tcctgcccct ggtcccagag 1860

cctcgccgcc tgcctgtggg gcccctgctc cgagcactgg ccacctgcca tgccctcagc 1920

cggctccagg acacccccgt gggcgacccc atggacttga agatggtgga gtctactggc 1980

tgggtcctgg aggaagagcc ggctgcagac tcagcatttg ggacccaggt cttggcagtg 2040

atgagacccc cactttggga gccccagctg caggcaatgg aggagccccc ggtgccagtc 2100

agcgtcctcc accgcttccc cttctcttcg gctctgcagc gcatgagtgt ggtggtggcg 2160

tggccagggg ccactcagcc cgaggcctac gtcaaaggct ccccggagct ggtggcaggg 2220

ctctgcaacc ccgagacagt gcccaccgac ttcgcccaga tgctgcagag ctatacagct 2280

gctggctacc gtgtcgtggc cctggccagc aagccactgc ccactgtgcc cagcctggag 2340

gcagcccagc aactgacgag ggacactgtg gaaggagacc tgagcctcct ggggctgctg 2400

gtcatgagga acctactgaa gccgcagaca acgccagtta tccaggctct gcgaaggacc 2460

cgcatccgcg ccgtcatggt gacaggggac aacctgcaga cagcggtgac tgtggcccgg 2520

ggctgtggca tggtggcccc ccaggagcat ctgatcatcg tccacgccac ccaccctgag 2580

cggggtcagc ctgcctctct cgagttcctg ccgatggagt cccccacagc cgtgaatggc 2640

gttaaggatc ctgaccaggc tgcaagctac accgtggagc cagacccccg atccaggcac 2700

ctggccctca gcgggcccac ctttggtatc attgtgaagc acttccccaa gctgctgccc 2760

aaggtcctgg tccagggcac tgtctttgcc cgcatggccc ctgagcagaa gacagagctg 2820

gtgtgcgagc tacagaagct tcagtactgc gtgggcatgt gcggagacgg cgccaatgac 2880

tgtggggccc tgaaggcggc tgatgtcggc atctcgctgt cccaggcaga agcctcagtg 2940

gtctcaccct tcacctcgag catggccagt attgagtgcg tgcccatggt catcagggag 3000

gggcgctgtt cccttgacac ttcgttcagc gtcttcaagt acatggctct gtacagcctg 3060

acccagttca tctccgtcct gatcctctac acgatcaaca ccaacctggg tgacctgcag 3120

ttcctggcca tcgacctggt catcaccacc acagtggcag tgctcatgag ccgcacgggg 3180

ccagcgctgg tcctgggacg ggtgcggcca ccgggggcgc tgctcagcgt gcccgtgctc 3240

agcagcctgc tgctgcagat ggtcctggtg accggcgtgc agctaggggg ctacttcctg 3300

accctggccc agccatggtt cgtgcctctg aacaggacag tggccgcacc agacaacctg 3360

cccaactacg agaacaccgt ggtcttctct ctgtccagct tccagtacct catcctggct 3420

gcagccgtgt ccaagggggc gcccttccgc cggccgctct acaccaatgt gcccttcctg 3480

gtggccctgg cgctcctgag ctccgtcctg gtgggccttg tcctggtccc cggcctcctg 3540

caggggccgc tggcgctgag gaacatcact gacaccggct tcaagctgct gctgctgggt 3600

ctggtcaccc tcaacttcgt gggggccttc atgctggaga gcgtgctaga ccagtgcctc 3660

cccgcctgcc tgcgccgcct ccggcccaag cgggcctcca agaagcgctt caagcagctg 3720

gaacgagagc tggccgagca gccctggccg ccgctgcccg ccggccccct gaggtagtgc 3780

aggcccacgg gcaccccaga cactggaact ccctgcctct gagccaccaa ctggacccct 3840

ctccagcaac accaccgcca ccacctccca catccctgag gttggcgact gtctacactc 3900

ctcccccgag accaccccca ccctggggaa gcgttgacta ctgtccccta ccttggacca 3960

tcccgcgtag gggtggcagc ccccagctcc cctcagtgct gctgtcagtg tagcaaataa 4020

agtcatgata ttttcctggc aaaaaaaaaa aaaaaaaaaa a 4061

<210> 2

<211> 1180

<212> PRT

<213> Homo sapiens

<400> 2

Met Ser Ala Asp Ser Ser Pro Leu Val Gly Ser Thr Pro Thr Gly Tyr

1 5 10 15

Gly Thr Leu Thr Ile Gly Thr Ser Ile Asp Pro Leu Ser Ser Ser Val

20 25 30

Ser Ser Val Arg Leu Ser Gly Tyr Cys Gly Ser Pro Trp Arg Val Ile

35 40 45

Gly Tyr His Val Val Val Trp Met Met Ala Gly Ile Pro Leu Leu Leu

50 55 60

Phe Arg Trp Lys Pro Leu Trp Gly Val Arg Leu Arg Leu Arg Pro Cys

65 70 75 80

Asn Leu Ala His Ala Glu Thr Leu Val Ile Glu Ile Arg Asp Lys Glu

85 90 95

Asp Ser Ser Trp Gln Leu Phe Thr Val Gln Val Gln Thr Glu Ala Ile

100 105 110

Gly Glu Gly Ser Leu Glu Pro Ser Pro Gln Ser Gln Ala Glu Asp Gly

115 120 125

Arg Ser Gln Ala Ala Val Gly Ala Val Pro Glu Gly Ala Trp Lys Asp

130 135 140

Thr Ala Gln Leu His Lys Ser Glu Glu Ala Val Ser Val Gly Gln Lys

145 150 155 160

Arg Val Leu Arg Tyr Tyr Leu Phe Gln Gly Gln Arg Tyr Ile Trp Ile

165 170 175

Glu Thr Gln Gln Ala Phe Tyr Gln Val Ser Leu Leu Asp His Gly Arg

180 185 190

Ser Cys Asp Asp Val His Arg Ser Arg His Gly Leu Ser Leu Gln Asp

195 200 205

Gln Met Val Arg Lys Ala Ile Tyr Gly Pro Asn Val Ile Ser Ile Pro

210 215 220

Val Lys Ser Tyr Pro Gln Leu Leu Val Asp Glu Ala Leu Asn Pro Tyr

225 230 235 240

Tyr Gly Phe Gln Ala Phe Ser Ile Ala Leu Trp Leu Ala Asp His Tyr

245 250 255

Tyr Trp Tyr Ala Leu Cys Ile Phe Leu Ile Ser Ser Ile Ser Ile Cys

260 265 270

Leu Ser Leu Tyr Lys Thr Arg Lys Gln Ser Gln Thr Leu Arg Asp Met

275 280 285

Val Lys Leu Ser Met Arg Val Cys Val Cys Arg Pro Gly Gly Glu Glu

290 295 300

Glu Trp Val Asp Ser Ser Glu Leu Val Pro Gly Asp Cys Leu Val Leu

305 310 315 320

Pro Gln Glu Gly Gly Leu Met Pro Cys Asp Ala Ala Leu Val Ala Gly

325 330 335

Glu Cys Met Val Asn Glu Ser Ser Leu Thr Gly Glu Ser Ile Pro Val

340 345 350

Leu Lys Thr Ala Leu Pro Glu Gly Leu Gly Pro Tyr Cys Ala Glu Thr

355 360 365

His Arg Arg His Thr Leu Phe Cys Gly Thr Leu Ile Leu Gln Ala Arg

370 375 380

Ala Tyr Val Gly Pro His Val Leu Ala Val Val Thr Arg Thr Gly Phe

385 390 395 400

Cys Thr Ala Lys Gly Gly Leu Val Ser Ser Ile Leu His Pro Arg Pro

405 410 415

Ile Asn Phe Lys Phe Tyr Lys His Ser Met Lys Phe Val Ala Ala Leu

420 425 430

Ser Val Leu Ala Leu Leu Gly Thr Ile Tyr Ser Ile Phe Ile Leu Tyr

435 440 445

Arg Asn Arg Val Pro Leu Asn Glu Ile Val Ile Arg Ala Leu Asp Leu

450 455 460

Val Thr Val Val Val Pro Pro Ala Leu Pro Ala Ala Met Thr Val Cys

465 470 475 480

Thr Leu Tyr Ala Gln Ser Arg Leu Arg Arg Gln Gly Ile Phe Cys Ile

485 490 495

His Pro Leu Arg Ile Asn Leu Gly Gly Lys Leu Gln Leu Val Cys Phe

500 505 510

Asp Lys Thr Gly Thr Leu Thr Glu Asp Gly Leu Asp Val Met Gly Val

515 520 525

Val Pro Leu Lys Gly Gln Ala Phe Leu Pro Leu Val Pro Glu Pro Arg

530 535 540

Arg Leu Pro Val Gly Pro Leu Leu Arg Ala Leu Ala Thr Cys His Ala

545 550 555 560

Leu Ser Arg Leu Gln Asp Thr Pro Val Gly Asp Pro Met Asp Leu Lys

565 570 575

Met Val Glu Ser Thr Gly Trp Val Leu Glu Glu Glu Pro Ala Ala Asp

580 585 590

Ser Ala Phe Gly Thr Gln Val Leu Ala Val Met Arg Pro Pro Leu Trp

595 600 605

Glu Pro Gln Leu Gln Ala Met Glu Glu Pro Pro Val Pro Val Ser Val

610 615 620

Leu His Arg Phe Pro Phe Ser Ser Ala Leu Gln Arg Met Ser Val Val

625 630 635 640

Val Ala Trp Pro Gly Ala Thr Gln Pro Glu Ala Tyr Val Lys Gly Ser

645 650 655

Pro Glu Leu Val Ala Gly Leu Cys Asn Pro Glu Thr Val Pro Thr Asp

660 665 670

Phe Ala Gln Met Leu Gln Ser Tyr Thr Ala Ala Gly Tyr Arg Val Val

675 680 685

Ala Leu Ala Ser Lys Pro Leu Pro Thr Val Pro Ser Leu Glu Ala Ala

690 695 700

Gln Gln Leu Thr Arg Asp Thr Val Glu Gly Asp Leu Ser Leu Leu Gly

705 710 715 720

Leu Leu Val Met Arg Asn Leu Leu Lys Pro Gln Thr Thr Pro Val Ile

725 730 735

Gln Ala Leu Arg Arg Thr Arg Ile Arg Ala Val Met Val Thr Gly Asp

740 745 750

Asn Leu Gln Thr Ala Val Thr Val Ala Arg Gly Cys Gly Met Val Ala

755 760 765

Pro Gln Glu His Leu Ile Ile Val His Ala Thr His Pro Glu Arg Gly

770 775 780

Gln Pro Ala Ser Leu Glu Phe Leu Pro Met Glu Ser Pro Thr Ala Val

785 790 795 800

Asn Gly Val Lys Asp Pro Asp Gln Ala Ala Ser Tyr Thr Val Glu Pro

805 810 815

Asp Pro Arg Ser Arg His Leu Ala Leu Ser Gly Pro Thr Phe Gly Ile

820 825 830

Ile Val Lys His Phe Pro Lys Leu Leu Pro Lys Val Leu Val Gln Gly

835 840 845

Thr Val Phe Ala Arg Met Ala Pro Glu Gln Lys Thr Glu Leu Val Cys

850 855 860

Glu Leu Gln Lys Leu Gln Tyr Cys Val Gly Met Cys Gly Asp Gly Ala

865 870 875 880

Asn Asp Cys Gly Ala Leu Lys Ala Ala Asp Val Gly Ile Ser Leu Ser

885 890 895

Gln Ala Glu Ala Ser Val Val Ser Pro Phe Thr Ser Ser Met Ala Ser

900 905 910

Ile Glu Cys Val Pro Met Val Ile Arg Glu Gly Arg Cys Ser Leu Asp

915 920 925

Thr Ser Phe Ser Val Phe Lys Tyr Met Ala Leu Tyr Ser Leu Thr Gln

930 935 940

Phe Ile Ser Val Leu Ile Leu Tyr Thr Ile Asn Thr Asn Leu Gly Asp

945 950 955 960

Leu Gln Phe Leu Ala Ile Asp Leu Val Ile Thr Thr Thr Val Ala Val

965 970 975

Leu Met Ser Arg Thr Gly Pro Ala Leu Val Leu Gly Arg Val Arg Pro

980 985 990

Pro Gly Ala Leu Leu Ser Val Pro Val Leu Ser Ser Leu Leu Leu Gln

995 1000 1005

Met Val Leu Val Thr Gly Val Gln Leu Gly Gly Tyr Phe Leu Thr Leu

1010 1015 1020

Ala Gln Pro Trp Phe Val Pro Leu Asn Arg Thr Val Ala Ala Pro Asp

1025 1030 1035 1040

Asn Leu Pro Asn Tyr Glu Asn Thr Val Val Phe Ser Leu Ser Ser Phe

1045 1050 1055

Gln Tyr Leu Ile Leu Ala Ala Ala Val Ser Lys Gly Ala Pro Phe Arg

1060 1065 1070

Arg Pro Leu Tyr Thr Asn Val Pro Phe Leu Val Ala Leu Ala Leu Leu

1075 1080 1085

Ser Ser Val Leu Val Gly Leu Val Leu Val Pro Gly Leu Leu Gln Gly

1090 1095 1100

Pro Leu Ala Leu Arg Asn Ile Thr Asp Thr Gly Phe Lys Leu Leu Leu

1105 1110 1115 1120

Leu Gly Leu Val Thr Leu Asn Phe Val Gly Ala Phe Met Leu Glu Ser

1125 1130 1135

Val Leu Asp Gln Cys Leu Pro Ala Cys Leu Arg Arg Leu Arg Pro Lys

1140 1145 1150

Arg Ala Ser Lys Lys Arg Phe Lys Gln Leu Glu Arg Glu Leu Ala Glu

1155 1160 1165

Gln Pro Trp Pro Pro Leu Pro Ala Gly Pro Leu Arg

1170 1175 1180

Claims

1. a kind of applications of ATP enzyme ATP13A2 in the behavior of preparation and dyskinesia detection marker, which is characterized in that described Behavior and dyskinesia are the amino acid sequence such as SEQ. of the ATP13A2 caused by nerve impulse control disorder and dyskinesia No. shown in 1.

2. application according to claim 1, which is characterized in that the nerve impulse control disorder and dyskinesia are because of ATP Enzyme ATP13A2 mutation cause serum sphingomyelin to reduce and ceramide raising.

3. application according to claim 1 or 2, which is characterized in that the nerve impulse control disorder and operating obstacle Including locomotor ataxia, paralysis, dementia and Parkinson's disease, spastic paralysi, neuron control systems With Kufor-Rakeb dementias.

4. a kind of compound FTY720 is applied in the drug for preparing treatment behavior and dyskinesia disease, the FTY720 chemistry Molecular formula is C₁₉H₃₃NO₂.HCl, molecular weight 343.94, which is characterized in that the behavior and dyskinesia are nerve impulse controls System is disorderly with caused by dyskinetic, and the compound includes its any modification or similar compound.

5. application according to claim 4, which is characterized in that the nerve impulse control disorder and operating obstacle include Locomotor ataxia, paralysis, dementia and Parkinson's disease, spastic paralysi, neuron control systems and Kufor-Rakeb dementias.

6. a kind of compound Fluoxetine is applied in the drug for preparing treatment behavior and dyskinesia disease, described Fluoxetine chemical molecular formulas are C₁₇H₁₈F₃NO.HCl, molecular weight 345.79, which is characterized in that the behavior and movement are different It is often caused by nerve impulse control disorder and dyskinetic, the compound includes its any modification or similar compound.

7. application according to claim 6, which is characterized in that the nerve impulse control is abnormal and operating obstacle includes Locomotor ataxia, paralysis, dementia and Parkinson's disease, spastic paralysi, neuron control systems and Kufor-Rakeb dementias.