Pub Date : 2025-12-02DOI: 10.1038/s41531-025-01180-z
Wenhua Sun, Claudia Schulte, Thomas Gasser, Manuela Tan
Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.
帕金森病（PD）的全基因组关联研究发现了与溶酶体机制相关的常见变异，包括TMEM175、SCARB2和CTSB。我们使用来自全球帕金森遗传学计划（GP2）的队列（来自10个祖先的33,733例病例和18,703例对照）调查了人群中常见和罕见变异之间的关系。在欧洲队列中，我们证实了三个基因中所有已知的遗传风险变异与PD风险的显著关联，TMEM175 p. Met393Thr是一个独立的全基因组显著信号。此外，还检测到一个新的独立信号SCARB2 rs11547135。在非裔美国人、德系犹太人和东亚人群中，负担分析将PD与SCARB2联系起来。基于单变异的检测在几个人群中发现了罕见的SCARB2错义变异。我们的研究强调了溶酶体遗传变异与帕金森病风险的关联，揭示了人群之间的遗传异质性。
{"title":"TMEM175, SCARB2 and CTSB associations with Parkinson's disease risk across populations.","authors":"Wenhua Sun, Claudia Schulte, Thomas Gasser, Manuela Tan","doi":"10.1038/s41531-025-01180-z","DOIUrl":"10.1038/s41531-025-01180-z","url":null,"abstract":"<p><p>Genome-wide association study of Parkinson's disease (PD) identified common variants associated with lysosomal mechanism, including TMEM175, SCARB2, and CTSB. We investigated the association between common and rare variants across populations using cohorts from the Global Parkinson's Genetics Program (GP2) (33,733 cases and 18,703 controls from ten ancestries). In the European cohort, we confirmed significant associations with PD risk for all known genetic risk variants across the three genes and TMEM175 p. Met393Thr as an independent genome-wide significant signal. Additionally, a novel independent signal, SCARB2 rs11547135, was detected. The burden analysis linked PD to SCARB2 in African American, Ashkenazi Jewish and East Asian cohorts. Single variants-based tests identified rare missense variants in SCARB2 in several populations. Our study reinforces the association of lysosomal genetic variants with PD risk, revealing genetic heterogeneity across populations.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":" ","pages":"348"},"PeriodicalIF":8.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12678402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1038/s41531-025-01155-0
Xuan Li,Si-Jia Peng,Yu Wang,Xin Chen,Ting-Ting Wu,Ya Feng,Xi-Xi Wang,Huiyong Yin,Yun-Cheng Wu
Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.
{"title":"ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson's disease.","authors":"Xuan Li,Si-Jia Peng,Yu Wang,Xin Chen,Ting-Ting Wu,Ya Feng,Xi-Xi Wang,Huiyong Yin,Yun-Cheng Wu","doi":"10.1038/s41531-025-01155-0","DOIUrl":"https://doi.org/10.1038/s41531-025-01155-0","url":null,"abstract":"Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"51 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1038/s41531-025-01181-y
Bahaaeddin Attaallah, Sheena Waters, Charles Marshall, Alastair Noyce
Neuropsychiatric symptoms are a significant yet often overlooked aspect of Parkinson’s disease (PD). Using UK Biobank data, we examined associations between neuropsychiatric dimensions and PD risk markers. Factor analysis identified four dimensions—Depression, Anxiety, Adult Stress-Adversity, and Alcohol- and Substance-Related Behaviours (ASRB) —across three groups: PD, healthy controls, and cerebrovascular disease (CVD) as neurological controls. These dimensions showed distinct patterns in PD. Depression scores were significantly elevated, while ASRB scores were consistently lower. Neuroimaging linked ASRB to subcortical changes specific to PD, particularly quantitative susceptibility mapping in the substantia nigra, consistent with the dopaminergic system’s role in goal-directed behaviour. GBA1 carrier status was linked to age-related changes in this dimension. Furthermore, PD patients with higher ASRB showed greater volatility in cognitive and motor function, with worsening before diagnosis and subsequent improvement. These findings highlight the complex interplay between psychiatric symptoms, neurobiological changes, and genetic factors in PD, suggesting that specific neuropsychiatric profiles may serve as early indicators of disease risk and progression.
{"title":"The relationship between neuropsychiatric dimensions and markers of Parkinson’s disease risk in the UK Biobank","authors":"Bahaaeddin Attaallah, Sheena Waters, Charles Marshall, Alastair Noyce","doi":"10.1038/s41531-025-01181-y","DOIUrl":"https://doi.org/10.1038/s41531-025-01181-y","url":null,"abstract":"Neuropsychiatric symptoms are a significant yet often overlooked aspect of Parkinson’s disease (PD). Using UK Biobank data, we examined associations between neuropsychiatric dimensions and PD risk markers. Factor analysis identified four dimensions—Depression, Anxiety, Adult Stress-Adversity, and Alcohol- and Substance-Related Behaviours (ASRB) —across three groups: PD, healthy controls, and cerebrovascular disease (CVD) as neurological controls. These dimensions showed distinct patterns in PD. Depression scores were significantly elevated, while ASRB scores were consistently lower. Neuroimaging linked ASRB to subcortical changes specific to PD, particularly quantitative susceptibility mapping in the substantia nigra, consistent with the dopaminergic system’s role in goal-directed behaviour. <jats:italic>GBA1</jats:italic> carrier status was linked to age-related changes in this dimension. Furthermore, PD patients with higher ASRB showed greater volatility in cognitive and motor function, with worsening before diagnosis and subsequent improvement. These findings highlight the complex interplay between psychiatric symptoms, neurobiological changes, and genetic factors in PD, suggesting that specific neuropsychiatric profiles may serve as early indicators of disease risk and progression.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"72 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1038/s41531-025-01191-w
Chao-Kai Hu, Walaa B. Mohammed, Yutong Bai, Franziska Schmidt, Tiffany A. Rodrigues, Suneil K. Kalia, Alfonso Fasano, Jürgen Germann, Paula Alcaide-Leon, Alexandre Boutet, Andres M. Lozano
{"title":"Limited predictive value of preoperative nigrosome integrity for motor outcomes in Parkinson’s disease deep brain stimulation","authors":"Chao-Kai Hu, Walaa B. Mohammed, Yutong Bai, Franziska Schmidt, Tiffany A. Rodrigues, Suneil K. Kalia, Alfonso Fasano, Jürgen Germann, Paula Alcaide-Leon, Alexandre Boutet, Andres M. Lozano","doi":"10.1038/s41531-025-01191-w","DOIUrl":"https://doi.org/10.1038/s41531-025-01191-w","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"8 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41531-025-01188-5
Longfei Wang, Michael Milton, Liam G. Fearnley, Oneil G. Bhalala, Melanie Bahlo, Haloom Rafehi
Repeat expansions (REs) may be Parkinson’s disease (PD) risk factors. We screened whole genome sequencing data from the AMP PD Lewy Body Dementia (LBD) and PD cohorts for 37 REs associated with neurological disorders, and identified both interrupted and uninterrupted REs in ATXN2 in 4/2431 PD and 2/2468 LBD cases, but none in controls. These findings support pleiotropy for certain REs in PD.
{"title":"Identification of expanded and interrupted ATXN2 repeat expansions in Parkinson’s disease and Lewy Body Dementia cohorts","authors":"Longfei Wang, Michael Milton, Liam G. Fearnley, Oneil G. Bhalala, Melanie Bahlo, Haloom Rafehi","doi":"10.1038/s41531-025-01188-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01188-5","url":null,"abstract":"Repeat expansions (REs) may be Parkinson’s disease (PD) risk factors. We screened whole genome sequencing data from the AMP PD Lewy Body Dementia (LBD) and PD cohorts for 37 REs associated with neurological disorders, and identified both interrupted and uninterrupted REs in <jats:italic>ATXN2</jats:italic> in 4/2431 PD and 2/2468 LBD cases, but none in controls. These findings support pleiotropy for certain REs in PD.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"18 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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