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Background: Knowledge of genetic determinants in Parkinson's disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach is exploited in this study.
Methods: Informative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of Parkinson's disease were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of variant(s) segregating with the phenotype were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest.
Results: Two compound heterozygous variants, a rare missense (c.1139C > T:p.P380L) and a novel splice variant (c.1456 + 2 delTAGA, intron10) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and two affected siblings. WASL, a gene not previously linked to a human Mendelian disorder is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased reactive oxygen species tolerance in mutation carrying cells on Tetrabutylphosphonium hydroxide induction and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants.
Conclusion: WASL, with demonstrated functional relevance in neurons may be yet another strong candidate gene for autosomal recessive PD encouraging assessment of its contribution across populations.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.001 | DOI Listing |
Acta Neurol Belg
December 2024
Department of Epidemiology and Biostatistics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Objectives: The purpose of this meta-analysis was to conduct a comparative study by systematically examining and analyzing trials that studied the impacts of levodopa and bromocriptine, either separately or together, in treating Parkinson's disease (PD).
Methods: An extensive literature search was conducted across PubMed (Medline), Scopus, and Web of Science databases, using targeted keywords for studies published up to October 2024. The methodological quality of included RCTs was assessed with the Cochrane Risk of Bias 2 (RoB 2) tool, and bias evaluation was performed using RevMan (version 5).
Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's disease (PD), occurring before widespread protein aggregation, neuronal loss, and cognitive decline. While the field has focused on the aggregation of Tau and α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even before their aggregation. Therefore, understanding the mechanisms by which Tau and α-Syn affect presynaptic terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses and potentially halting neurodegeneration.
View Article and Find Full Text PDFAnal Chem
December 2024
Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Nanoscale aggregates play a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. However, quantifying these aggregates in complex biological samples, such as biofluids and postmortem brain tissue, has been challenging due to their low concentration and small size, necessitating the development of methods with high sensitivity and specificity. Here, we have developed ultrasensitive assays utilizing the Quanterix Simoa platform to detect α-synuclein, β-amyloid and tau aggregates, including those with common posttranslational modifications such as truncation of α-synuclein and AT8 phosphorylation of tau aggregates.
View Article and Find Full Text PDFClin Neurophysiol
December 2024
Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Edmond J. Safra Program in Parkinson's Disease, University Health Network, Toronto, Ontario, Canada.
On July 6th of 1924 Hans Berger -a German psychiatrist- first recorded electric signals from the human brainvia scalp electrodes. This date marks the beginning of Electroencephalography. In this review a representative panel of past and present Officers of the International Federation of Clinical Neurophysiology (IFCN) and of its Official Journal briefly summarizes the past, present and future of Electroencephalographic and related neurophysiological techniques' impact and the role of the IFCN in global collaboration, education, standardization, research innovation, and clinical practice.
View Article and Find Full Text PDFDisabil Rehabil
December 2024
School of Psychology, Trinity College Dublin, Dublin, Ireland.
Background: People with young-onset Parkinson's disease (YOPD), a term for those diagnosed with Parkinson's disease (PD) under the age of 60, face unique challenges compared to those diagnosed with PD later in life. A better understanding of the lived experience of those with YOPD is essential to delivering bespoke rehabilitation and improving quality of life.
Purpose: To provide insight into the emotional and social lived experience of individuals with YOPD.
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