African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1 DOI Creative Commons
Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(12), P. 1955 - 1963

Published: Dec. 1, 2024

Abstract Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase ( GBA1 ). This variant rs3115534 -G) is carried by ~50% of West PD cases and imparts a dose-dependent increase in for disease. The has varied frequencies across ancestry groups but almost absent European Asian populations. high clinical therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher monoallelic confer dementia with Lewy bodies, likely reducing function glucocerebrosidase. Interestingly, noncoding variant, suggesting different mechanism action. Using full-length RNA transcript sequencing, we partial intron 8 expression carriers (G) not nonvariant (T). Antibodies targeting N terminus showed that this intron-retained isoform protein coding subsequent proteomics did identify shorter isoform, based. Clustered regularly interspaced short palindromic repeats editing reported index ) revealed sequence alteration responsible driving production these transcripts containing 8. Follow-up analysis it key intronic branchpoint and, therefore, important implications splicing In addition, when measuring activity, reduction carriers. Overall, report functional effect which acts interfering transcripts, resulting reduced levels activity. understanding reveals potential target underserved underrepresented population.

Language: Английский

Towards a Global View of Parkinson's Disease Genetics DOI Creative Commons
Marzieh Khani, Catalina Cerquera‐Cleves, Mariam Kekenadze

et al.

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(5), P. 831 - 842

Published: April 1, 2024

Parkinson's disease (PD) is a global health challenge, yet historically studies of PD have taken place predominantly in European populations. Recent genetics research conducted non-European populations has revealed novel population-specific genetic loci linked to risk, highlighting the importance studying globally. These insights broadened our understanding etiology, which crucial for developing disease-modifying interventions. This review comprehensively explores landscape PD, emphasizing scientific rationale underrepresented It underscores challenges, such as genotype-phenotype heterogeneity and inclusion difficulties participants, ongoing need diverse inclusive PD. ANN NEUROL 2024;95:831-842.

Language: Английский

Citations

15
Genetic heterogeneity of early onset Parkinson disease: The dilemma of clinico-genetic correlation DOI
Roopa Rajan, Vikram V. Holla,

Nitish Kamble

et al.

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: unknown, P. 107146 - 107146

Published: Sept. 1, 2024

Language: Английский

Citations

4
Clinico-genetic analysis of patients with LRRK2-related Parkinson’s disease from a referral centre in India DOI

Shivani Rath,

Vikram V. Holla, Prashant Phulpagar

et al.

Parkinsonism & Related Disorders, Journal Year: 2025, Volume and Issue: unknown, P. 107299 - 107299

Published: Jan. 1, 2025

Language: Английский

Citations

0
Deciphering the Genetic Architecture of Parkinsons Disease in India DOI Open Access
Asha Kishore, Ashwin Ashok Kumar Sreelatha, Amabel Tenghe

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Abstract The genomic landscape of the Indian population, particularly for age-related disorders like Parkinson’s disease (PD) remains underrepresented in global research. Genetic variability PD has been studied predominantly European populations, offering limited insights into its role within population. To address this gap, we conducted first pan-India survey involving 4,806 cases and 6,364 controls, complemented by a meta-analysis integrating summary statistics from multi-ancestry (N=611,485). We further leveraged RNA-sequencing data lymphoblastoid cell lines 731 individuals 1000 Genomes project to evaluate expression key loci across populations. Our findings reveal higher genetic burden population compared Europeans, accounting ∼30% previously unexplained heritability. Thirteen genome-wide significant were identified, including two novel loci, with an additional three uncovered through meta-analysis. Polygenic risk score analysis showed moderate transferability results highlight importance immune function, lipid metabolism SNCA aggregation pathogenesis, gene emphasizing population-specific differences. also established South Asia’s largest biobank, providing foundation patient-centric approaches research treatment India.

Language: Английский

Citations

0
Bassoon, Presynaptic Scaffolding Protein: Narrative Review in Health and Disease DOI

Ahamed P. Kaladiyil,

Prashanth Lingappa Kukkle

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(5)

Published: March 1, 2025

ABSTRACT The release of synaptic vesicles (SVs) at the junction is a complex process involving various specialized proteins that work in unison. Among these, Bassoon has emerged as significant protein, particularly noted for its association with neurological and aging‐related diseases. Due to structural functional roles, become focus recent research, especially understanding implications neurodegenerative psychiatric disorders. In this narrative review, we explore Bassoon's structure, function, role across spectrum Neurotransmission tightly regulated relies on structures within presynaptic terminal, such active zone (AZ), precisely control SV response incoming signals. AZ comprises network large, multidomain proteins, playing crucial arrangement. facilitates tethering reloading SVs, ensuring responsiveness high‐frequency signals, while also maintaining proteostasis presynapse. This involves orchestrating localization essential neuronal development plasticity. large size unique features enable it interact regulate function multiple making integral functioning. Variants gene have been linked variety conditions, including Progressive Supranuclear Palsy, system atrophy (MSA), epilepsy, schizophrenia, bipolar disorder, Parkinson's disease. review delves into pivotal preserving integrity how disruptions functions may contribute these

Language: Английский

Citations

0
Genetic study of the NUS1 gene variants in Han Chinese patients with Parkinson’s disease DOI Open Access

Cui Gao,

Lamei Yuan, Wen Zheng

et al.

Ageing and Neurodegenerative Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Aim: Parkinson’s disease (PD) is the second most common progressive neurodegenerative linked to genetic and other factors. The NUS1 dehydrodolichyl diphosphate synthase subunit gene (NUS1) variants were reported be associated with PD. In this PD-control cohort, we aimed explore potential role of in Methods: A cohort 512 Han Chinese sporadic PD patients 516 ethnically age-matched controls underwent clinical evaluation. Peripheral blood samples then collected, whole-exome sequencing was performed. PD-related identified through screening verified using Sanger sequencing, further classified, subsequently analyzed by bioinformatics analysis tools. Statistical conducted assess association between Results: Three heterozygous missense variants, including c.127G>T (p.Ala43Ser, rs1327892878), c.487G>C (p.Asp163His, rs369403261), c.537T>A (p.Asp179Glu, rs28362519), identified. Two rare c.487G>C, exclusively found patients, while low-frequency variant detected both controls. Combined analysis, a potentially pathogenic may exert risk, though no significant shown statistical (all P > 0.05). Conclusion: Our findings suggested that seem not cause monogenic PD, like may, at most, susceptibility

Language: Английский

Citations

0
Cryo-EM structures of filaments from the brains of individuals with variants G51D and H50Q in α-synuclein DOI
Yang Yang,

Alexey G. Murzin,

Thomas G. Hinton

et al.

Published: May 9, 2025

Abstract Gene dosage and point mutations in SNCA, the a-synuclein gene, give rise to familial forms of Parkinson’s disease dementia with Lewy bodies; an insertion mutation SNCA causes juvenile-onset synucleinopathy. We previously reported electron cryo-microscopy (cryo-EM) structures filaments from brains individuals disease, bodies multiple system atrophy, as well brain individual Here we report cryo-EM frontal cortex two cases Parkinsonism G51D those amygdala a case variant H50Q a-synuclein. The assembled consist identical protofilaments fold island B, but without identified disconnected density A. protofilament interface is made residues E46, V48 H50. Filaments comprise single both islands A B. Unlike G51D, pathogenicity has been questioned. It remains be seen if dimerisation may also underlie other missense Moreover, have right-handed helical twist, while atrophy synucleinopathy are left-handed, which significant.

Language: Английский

Citations

0
Pathological study of progressive supranuclear palsy the cases with mutations in Bassoon DOI

Masahiro Wakita,

Hiroaki Yaguchi,

Mika Otuski

et al.

Neuropathology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence neurofibrillary tangles (NFTs) accumulation phosphorylated tau protein neurons glial cells brain. We previously identified point mutation p.Pro3866Ala Bassoon ( BSN ) gene a Japanese family PSP‐like syndrome. newly detected mutations two autopsied cases carrying p.Thr2542Met p.Glu2759Gly, respectively. The case showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, parkinsonism. Brain magnetic resonance imaging (MRI) atrophy midbrain tegmentum hippocampus. Pathologically, moderate severe gliosis was also found substantia nigra, there an almost complete transitional zone cornu ammonis (CA) 1 region subiculum. NFTs were observed globus pallidus, subthalamic nucleus, CA1. 4R tau‐dominant tauopathy detected. p.Glu2759Gly symptoms, right‐dominant motor impairment, right limping gait, postural instability, dysfunction. MRI mild left‐dominant parietal lobe atrophy. thalamus, putamen, tegmentum. Most immunopositive for four‐repeat tau, whereas only few them harbored three‐repeat tau‐positive results pathological study mutations; these new cases. clinical phenotypes similar first symptoms. Accumulation dominant. Further autopsies further elucidation molecular biological mechanism are desirable.

Language: Английский

Citations

2
Behavioral and histological analyses of the mouse Bassoon p.P3882A mutation corresponding to the human BSN p.P3866A mutation DOI Creative Commons
Daiki Tanaka, Hiroaki Yaguchi, Kaichi Yoshizaki

et al.

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: July 26, 2024

Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy triggered remains elucidated. We previously identified point mutation c.11596C > G, p.Pro3866Ala

Language: Английский

Citations

1
African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1 DOI Creative Commons
Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 24, 2024

Abstract Recently, a novel African ancestry specific Parkinson’s disease (PD) risk signal was identified at the gene encoding glucocerebrosidase ( GBA1 ). This variant (rs3115534-G) is carried by ∼50% of West PD cases and imparts dose-dependent increase in for disease. The has varied frequencies across groups, but almost absent European Asian populations. high clinical therapeutic interest. Damaging bi-allelic protein-coding variants cause Gaucher mono-allelic confer Dementia with Lewy Bodies, likely reducing function glucocerebrosidase. Interestingly, non-coding variant, suggesting different mechanism action. Using full length RNA transcript sequencing, we intron 8 expression carriers (G) not non-variant (T). Antibodies targeting N-terminus showed that this intron-retained isoform protein coding subsequent proteomics did identify shorter isoform, RNA-based. CRISPR editing reported index (rs3115534) revealed responsible sequence alteration driving production these containing transcripts. Follow-up analysis it key intronic branchpoint therefore important implications splicing In addition, when measuring activity reduction (G). Overall, report functional effect which acts interfering transcripts, resulting reduced levels activity. understanding reveals target an underserved underrepresented population.

Language: Английский

Citations

1