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}
Pub Date : 2025-11-27DOI: 10.1038/s41531-025-01215-5
Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed, Jackson G. Schumacher, Jae Ahn, Leilei Shi, Yujia Wang, Yukun Tan, Jiayin Zhang, Ken Chen, Hussein Tawbi, Jian Wang, Michael A. Schwarzschild, Weiyi Peng, Xiqun Chen
Mutations in LRRK2 , a leading genetic cause of Parkinson’s disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples ( n = 651) and matched CSF samples ( n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of LRRK2 status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in LRRK2 mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies.
{"title":"Soluble immune factor profiles in blood and CSF associated with LRRK2 mutations and Parkinson’s disease","authors":"Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed, Jackson G. Schumacher, Jae Ahn, Leilei Shi, Yujia Wang, Yukun Tan, Jiayin Zhang, Ken Chen, Hussein Tawbi, Jian Wang, Michael A. Schwarzschild, Weiyi Peng, Xiqun Chen","doi":"10.1038/s41531-025-01215-5","DOIUrl":"https://doi.org/10.1038/s41531-025-01215-5","url":null,"abstract":"Mutations in <jats:italic>LRRK2</jats:italic> , a leading genetic cause of Parkinson’s disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples ( <jats:italic>n</jats:italic> = 651) and matched CSF samples ( <jats:italic>n</jats:italic> = 129) from <jats:italic>LRRK2</jats:italic> mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, <jats:italic>LRRK2</jats:italic> mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of <jats:italic>LRRK2</jats:italic> status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in <jats:italic>LRRK2</jats:italic> mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609167","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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