A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease

Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.

Polymorphism analysis of PARK2 gene mutations in Han Chinese patients with early-onset Parkinson's disease

The PARK2 gene is a common disease gene in Han Chinese patients with Parkinson＇s disease.The detection of mutations in the PARK2 gene remains low.To investigate the role PARK2 gene mutations play in the pathogenesis of Parkinson＇s disease,30 Han Chinese patients with early-onset Parkinson＇s disease and 38 normal controls were studied to determine the sequence changes of 1,4,6 and 7 exon sections.In the 30 patients with Parkinson＇s disease,a heterozygous intron mutation（nt 119,G→G/A）in exon 1 was detected in one case;a homozygous intron mutation（nt 526500,T→C）between intron 3 and exon 4 in fourteen cases was found;a heterozygous intron mutation（nt 526607,G→G/A）between intron 3 and exon 4 was observed in eight cases;an exon 6missense mutation（nt 754317,C→C/T;codon 193,CGG→CGG/TGG;aa 193,Arg→Arg/Trp）in three cases was seen;and an exon 7 missense mutation（nt 941943,C→A/C;codon 272,CTC→CTC/ATC;aa 272,Leu→Leu/lle）was found in one case.These changes were not found in the normal population.The results indicated that the PARK2 exons 6 and 7 mutations are possibly pathogenic mutations,along with the intron 3-exert 4 and exon 1 mutations.PARK2 gene mutations are possible factors leading to the onset of Parkinson＇s disease.

Association of Nurr1 gene mutations with Parkinson's disease in the Han population living in the Hubei province of China

Nurr1 defects could in part underlie Parkinson’s disease pathogenesis,and Nurr1 gene polymorphism has been found in Caucasian patients with Parkinson’s disease.In this study,heteroduplex technology was applied to compare the DNA sequences of eight exons of Nurr1 among 200 sporadic Parkinson’s disease patients and 200 healthy controls in the Han population in the Hubei province,China.One allele amplified from exon 3 of Nurr1 was polymorphic in five Parkinson’s disease patients（2.5%,5/200）,and two individuals had a polymorphic allele amplified from exon 2 （1%,2/200）.The anomalous electrophoresis fragment in exon 3 of Nurr1 gene contained a 709C/A missense mutation,and a polymorphic single nucleotide polymorphism at 388G/A was identified in exon 2.Compared with the control group,the Nurr1 gene expression level in the Parkinson’s disease group was decreased,and the Nurr1 gene expression levels in Parkinson’s disease patients carrying the polymorphisms at exons 2 and 3 were significantly decreased.Our data indicate that the single nucleotide polymorphism 388G/A in exon 2 and the 709C/A missense mutation in exon 3 of the Nurr1 gene in the Chinese population might affect the pathogenesis of Parkinson’s disease.

Pathogenic genes associated with Parkinson’s disease:molecular mechanism overview

Parkinson’s disease(PD)is a common neurodegenerative disease in the elderly,accounting for more than 1%of the population aged 65 years.Monogenic inheritance is relatively rare in PD,accounting for approximately 5%to 10%of PD patients,and there is a growing body of evidence suggesting that multiple genetic risk factors play a significant role in the pathogenesis of PD.Several groups have identified and reported a number of genes carrying mutations associated with affected family members.Mutated genes associated with PD are also candidates for idiopathic PD,and these genes may also carry other mutation sites that increase risk.When multiple genetic risk factors are combined,the risk of PD is increased to a greater extent,and to unravel the pathogenic pathways that lead to different forms of PD.This review focuses on the association of PD genes,such as Parkinson Disease 1-24(PARK1-24),glucosylceramidase(GBA),GTP cyclohydrolase 1(GCH1),fibroblast growth factor 20(FGF20),nuclear receptor-related factor 1(NURR1),NUS1 dehydrodolichyl diphosphate synthase subunit(NUS1),diacylglycerol Lipase Beta(DAGLB),transmembrane protein(TMEM),ubiquinol-cytochrome c reductase core protein 1(UQCRC1),glycoprotein non-metastatic melanoma protein B protein(GPNMB),dynactin 1(DCTN1),LDL receptor related protein 10(LRP10),monoamine oxidase(MAO),ataxin 2(ATXN2),microtubule associated protein tau(MAPT),pantothenate kinase 2(PANK2),spastic parapplegia type 11(SPG11),polymer gamma(POLG),TATA-box binding protein associated factor 1(TAF1),dual specificity tyrosine phosphorylation regulated kinase 1A(Dyrk1a),and crystallin alpha A(CRYAA),with the pathogenesis of PD.We introduce what is currently known about the molecular genetics of PD to help explain the molecular mechanisms leading to the neurodegenerative disease.

PARK1 gene mutation of autosomal dominant Parkinson's disease family

Studies have shown that PARK1 gene is associated with the autosomal dominant inheritance of Parkinson＇s disease. PARK1 gene contains two mutation sites, namely Ala30Pro and Ala53Thr, which are located on exons 3 and 4, respectively. However, the genetic loci of the pathogenic genes remain unclear. In this study, blood samples were collected from 11 members of a family with high prevalence of Parkinson＇s disease, including four affected cases, five suspected cases and two non-affected cases. Point mutation screening of common mutation sites on PARK1 gene exon 4 was conducted using PCR, to determine the genetic loci of the causative gene for Parkinson＇s disease. Gene identification and sequencing results showed that a T base deletion mutation was observed in the PARK1 gene exon 4 of all 11 collected samples. It was confirmed that the PARK1 gene exon 4 gene mutation is an important pathogenic mutation for Parkinson＇s disease.

Parkin and <i>LRRK2</i>/Dardarin Mutations in Early Onset Parkinson’s Disease in the Basque Country (Spain)

We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) with an age at onset younger than 50 years (EOPD), living in Gipuzkoa (Basque Country, Spain). Thirteen of them (48%) were PRKN2 mutation carriers. The c.255-256DelA mutation was the most frequent, followed by a deletion involving exons 3 and 4. A deletion involving exons 3 and 12 of the PRKN2 gene and R1441G LRRK2 mutation was found together in one PD patient. Four out of fourteen PRKN2 negative patients carried the p.G2019S mutation. Both PRKN2 mutation carriers and non-carriers presented frequently with family history (10 PRKN2 mutation carriers and 8 PRKN2 non-carriers);in fact, five patients without a known gene mutation had a first degree relative affected, suggesting another monogenic disease. PRKN2 carriers presented with a younger age at onset (36.7 vs. 41.7) and more benign disease progression. Indeed, those PD patients younger than forty who initially presented with unilateral tremor became shortly bilateral. Relatively, symmetric parkinsonism and slow disease progression carried more frequently PRKN2 mutations than patients with unilateral akinetic rigid parkinsonism and age at onset later than 40 years. As expected in a recessive disease, PRKN2 patients present more often with affected siblings and unaffected patients. The G2019S LRRK2 mutation, less prevalent than R1441G in our area, may be also a frequent cause of PD in EOPD (4 patients).

Point Mutation in the Parkin Gene on Patients with Parkinson's Disease

To investigate the distribution of possible novel mutations from parkin gene in variant subset of patients with Parkinson's disease (PD) in China and explore whether parkin gene plays an important role in the pathogenesis of PD, 70 patients were divided into early-onset group and late-onset group; 70 healthy subjects were included as controls. Genomic DNA from 70 normal controls and from those of PD patients were extracted from peripheral blood leukocytes by using standard procedures. Mutations of parkin gene (exon 1-12) in all the subjects were screened by PCR-single strand conformation polymorphism (SSCP). and further sequencing was performed in the samples with abnormal SSCP results, in order to confirm the mutation and its location. A new missense mutation Gly284Arg in a patient and 3 abnormal bands in SSCP electrophoresis from samples of another 3 patients were found. All the DNA variants were sourced from the samples of the patients with early-onset PD. It was concluded that Parkin point mutation also partially contributes to the development of early-onset Parkinson's disease in Chinese.

Analysis of known point mutations and SNPs in genes responsible for monogenic Parkinson’s disease in Russian patients

Background: Parkinson’s disease (PD) is caused by complex interactions between genetic and environmental factors. Mendelian forms of PD rarely occur in practice, but respective genes may play some role in pathogenesis of a common sporadic form of the disease. Methods: We analyzed most frequent known point mutations (PMs) and single-nucleotide polymorphisms (SNPs) in genes responsible for monogenic PD in 408 Russian patients, using arrayed primer extension (APEX), real-time PCR, and restriction fragment length polymorphism analysis. Results: We detected only three heterozygous PMs in the PARK2 gene in three non-related patients with early-onset sporadic PD. No association between PD and the studied SNPs was identified. Conclusion: The examined PMs and SNPs in genes responsible for monogenic PD do not contribute significantly to the development of sporadic PD in Russia.

Exon Deletions of Parkin Gene in Patients with Parkinson Disease

Summary: Mutations in the parkin gene have recently been identified in familial and isolated patients with early-onset Parkinson disease (PD) and that subregions between exon 2 and 4 of the parkin gene are hot spots of deletive mutations. To study the distribution of deletions in the parkin gene among variant subset patients with PD in China, and to explore the role of parkin gene in the pathogenesis of PD, 63 patients were divided into early onset and later onset groups. Exons 1-12 were amplified by PCR, templated by the genomic DNA of patients, and then the deletion distribution detected by agarose electrophoresis. Four patients were found to be carrier of exon deletions in 63 patients with PD. The location of the deletion was on exon 2 (1 case), exon 3 (2 cases) and exon 4 (1 case). All patients were belong to the group of early onset PD. The results showed that parkin gene deletion on exon 2, exon 3 and exon 4 found in Chinese population contributes partly to early onset PD.

Is activation of GDNF/RET signaling the answer for successful treatment of Parkinson's disease?A discussion of data from the culture dish to the clinic

The neurotrophic signaling of glial cell line-derived neurotrophic factor(GDNF)with its canonical receptor,the receptor tyrosine kinase RET,coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models.This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain.Despite several clinical trials with GDNF in Parkinson’s disease patients,which mainly focused on optimizing the GDNF delivery technique,benefits were only seen in a few patients.In general,the endpoints did not show significant improvements.This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic.Here we will refer to the latest publications and point out important open questions in the field.

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles

The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

Mitophagy in neurodegenerative disease pathogenesis

Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Parkin Somatic Mutations Link Melanoma and Parkinson's Disease

Epidemiological studies suggest a direct link between melanoma and Parkinson＇s disease（PD）; however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28 K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson＇s disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.

Impact of gene mutation in the development of Parkinson’s disease

Parkinson’s disease(PD)is the second most common age related neurodegenerative disorder worldwide and presents as a progressive movement disorder.Globally seven million to 10 million people have Parkinson’s disease.Parkinsonism is typically sporadic in nature.Loss of dopaminergic neurons from substantia nigra pars compacta(SNpc)and the neuronal intracellular Lewy body inclusions are the major cause of PD.Gene mutation and protein aggregation play a pivotal role in the degeneration of dopamine neurons.But the actual cause of dopamine degeneration remains unknown.However,several rare familial forms of PD are associated with genetic loci,and the recognition of causal mutations has provided insight into the disease process.Yet,the molecular pathways and gene transformation that trigger neuronal susceptibility are inadequately comprehended.The discovery of a mutation in new genes has provided a basis for much of the ongoing molecular work in the PD field and testing of targeted therapeutics.Single gene mutation in a dominantly or recessively inherited gene results a great impact in the development of Parkinson’s disease.In this review,we summarize the molecular genetics of PD.

Parkin基因S/N167多态性与帕金森病发病风险的Meta-分析

目的 运用Meta 分析的方法综合评价parkin基因S/N16 7多态性与帕金森病 (PD)发病的关系。 方法 检索Medline、Cochrane图书馆 (英文 )和中国生物医学文献数据库 (CBM ) (中文 ) ,纳入内容涉及parkin基因S/N16 7多态的基因型频率和 (或 )等位基因频率的独立病例对照研究 ,同时手检并纳入了我们研究组未发表的文献。各文献满足研究方法相似 ,有综合的统计指标。研究年限为 1998～ 2 0 0 3年。语种不限。排除不符合纳入标准 ,未涉及S/N16 7多态基因频率的对照研究。应用RevMan4 .2软件进行统计分析。结果 合并统计 ,总体效应检验未发现统计学上的差异 (Z =1.5 7,P =0 .12 ) ,但根据东西方人群进行分组分析后发现 ,S/N16 7多态在基因型水平 [OR =1.4 1,95 %CI =(1.0 8,1.83) ,P =0 .0 1]和等位基因水平 [OR =1.2 5 ,95 %CI=(1.0 8,1.4 4 ) ,P =0 .0 1]均可能增加东方人群患PD的发病风险。加入我们研究组的未发表资料后 ,上述结论未改变 ,趋势更明显。而西方人群在基因型水平 [OR =0 .5 5 ,95 %CI =(0 .30 ,1.0 2 ) ,P =0 .0 6 ]和等位基因水平 [OR =0 .5 5 ,95 %CI =(0 .2 8,1.0 8) ,P =0 .0 8]均无统计学上的差异。结论 我们的Meta 分析结果提示 ,S/N16 7多态性可能增加了东方人群患PD的危险性 ,对西?

The association between Parkinson’s disease and melanoma: a systematic review and meta-analysis

Objective:To assess the association between Parkinson’s disease(PD)and melanoma via systematic review and meta-analysis.Methods:Comprehensive search in PubMed,Web of Science,Embase and four China databases(SinoMed,WanFang data,CNKI and VIP database)of epidemiologic evidences on PD and melanoma published before April 30,2015.Studies which reported risk estimates of melanoma among PD patients or risk estimates of PD in patients with melanoma were included.Pooled odds ratios(ORs)with 95%confidence intervals(CIs)were calculated by random-effects models.Heterogeneity across studies was assessed using Cochran Q and I2 statistics.Subgroup analyses and sensitivity analyses were conducted to evaluate sources of heterogeneity.Subgroup analyses were done according to temporal relationship,geographic region and gender respectively.We assessed publication bias using the Begg and Egger test.In addition,study appraisal was done using a scale for observational studies to ensure the quality of evidence.Results:We identified 24 eligible studies on PD and melanoma with a total number of 292,275 PD patients:the pooled OR was 1.83(95%CI 1.46–2.30)overall,subgroup analyses by temporal relationship showed that risk of melanoma after PD diagnosis was significantly higher(OR 2.43,95%CI 1.77–3.32),but not before the diagnosis of PD(OR 1.09,95%CI 0.78–1.54).Subgroup analysis by geographic region showed that increased risk of melanoma in PD was found both in Europe(OR 1.44,95%CI 1.22–1.70)and in North America(OR 2.64,95%CI 1.63–4.28).Gender-specific subgroup analyses did not show difference between men(OR 1.64,95%CI 1.27–2.13)and women(OR 1.38,95%CI 1.04–1.82)in the risk of melanoma.In addition,we found the risk of non-melanoma skin cancers in PD was slightly higher(OR 1.20,95%CI 1.11–1.29)than general population.It was impossible to evaluate the association between PD and melanoma according to use of levodopa or gene polymorphism via meta-analysis since few observational or cohort studies have focused on it.Conclusions:An association between PD and melanoma was confirmed.Most of the evidences were of high quality,and the conclusion was robust.Further research is needed to explore the mechanisms underlying this relationship.

Dysregulation of autophagy and mitochondrial function in Parkinson’s disease

Parkinson’s disease(PD)is the second most common neurodegenerative disease.Increasing evidence supports that dysregulation of autophagy and mitochondrial function are closely related with PD pathogenesis.In this review,we briefly summarized autophagy pathway,which consists of macroautophagy,microautophagy and chaperone-mediated autophagy(CMA).Then,we discussed the involvement of mitochondrial dysfunction in PD pathogenesis.We specifically reviewed the recent developments in the relationship among several PD related genes,autophagy and mitochondrial dysfunction,followed by the therapeutic implications of these pathways.In conclusion,we propose that autophagy activity and mitochondrial homeostasis are of high importance in the pathogenesis of PD.Better understanding of these pathways can shed light on the novel therapeutic methods for PD prevention and amelioration.

Premotor biomarkers for Parkinson's disease-a promising direction of research

The second most serious neurodegenerative disease is Parkinson’s disease(PD).Over the past several decades,a strong body of evidence suggests that PD can begin years before the hallmark clinical motor symptoms appear.Biomarkers for PD are urgently needed to differentiate between neurodegenerative disorders,screen novel therapeutics,and predict eventual clinical PD before the onset of symptoms.Some clinical evaluations and neuroimaging techniques have been developed in the last several years with some success in this area.Moreover,other strategies have been utilized to identify biochemical and genetic markers associated with PD leading to the examination of PD progression and pathogenesis in cerebrospinal fluid,blood,or saliva.Finally,interesting results are surfacing from preliminary studies using known PD-associated genetic mutations to assess potential premotor PD biomarkers.The current review highlights recent advances and underscores areas of potential advancement.

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

Altered Motor Performance,Sleep EEG,and Parkinson’s Disease Pathology Induced by Chronic Sleep Deprivation in Lrrk2^(G2019S) Mice

Parkinson’s disease(PD)is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic(DAergic)neuron loss in the substantia nigra pars compacta.The mutation of leucine-rich repeat kinase 2(Lrrk2)is the most common autosomal dominant mutation in PD,and it has also been reported in sporadic cases.A growing body of research suggests that circadian rhythm disruption,particularly sleep-wake abnormality,is common during the early phase of PD.Our present study aimed to evaluate the impact of sleep deprivation(SD)on motor ability,sleep performance,and PD pathologies in Lrrk2^(G2019S) transgenic mice.After two months of SD,Lrrk2^(G2019S) mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits,a reduced striatal DA level,degenerated DAergic neurons,and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain.All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up.Moreover,a significant increase inα-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age.Taken together,our findings indicate that sleep abnormalities,as a risk factor,may contribute to the pathogenesis and progression of PD.Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.