Abstract
Sporadic Parkinson’s disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) are neurodegenerative diseases characterized by progressive and selective neuron death, with some genetic similarities. In order to investigate the genetic risk factors common to both sPD and sALS, we carried out a screen of risk alleles for sALS and related loci in 530 sPD patients and 530 controls from the Han population of Mainland China (HPMC). We selected 27 single-nucleotide polymorphisms in 10 candidate genes associated with sALS, and we performed allelotyping and genotyping to determine their frequencies in the study population as well as bioinformatics analysis to assess their functional significance in these diseases. The minor alleles of rs17115303 in DAB adaptor protein 1 (DAB1) gene and rs6030462 in protein tyrosine phosphatase receptor type T (PTPRT) gene were correlated with increased risk of both sPD and sALS. Polymorphisms of rs17115303 and rs6030462 were associated with alterations in transcription factor binding sites, secondary structures, long non-coding RNA interactions, and nervous system regulatory networks; these changes involved biological processes associated with neural cell development, differentiation, neurogenesis, migration, axonogenesis, cell adhesion, and metabolism of phosphate-containing compounds. Thus, variants of DAB1 gene (rs17115303) and PTPRT gene (rs6030462) are risk factors common to sPD and sALS in the HPMC. These findings provide insight into the molecular pathogenesis of both diseases and can serve as a basis for the development of targeted therapies.
Highlights
Sporadic Parkinson’s disease is a disorder caused by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra (SN) projecting to the striatum and containing cytoplasmic inclusions (Spillantini et al, 1997) that are mainly composed of α-synuclein protein (Stefanis, 2012)
We found that DAB adaptor protein 1 (DAB1) rs17115303 and phosphatase receptor type T (PTPRT) rs6030462 mutations are common to Sporadic Parkinson’s disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) and may play causative roles in the pathogenesis of both diseases
This was confirmed by the results of the Gene Ontology (GO) analysis, which showed that the two genes have overlapping functions in development, differentiation, neurogenesis, migration, axonogenesis, adhesion, and the metabolism of phosphate-containing compounds
Summary
Sporadic Parkinson’s disease (sPD) is a disorder caused by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra (SN) projecting to the striatum and containing cytoplasmic inclusions (Spillantini et al, 1997) that are mainly composed of α-synuclein protein (Stefanis, 2012). SALS affects motor neurons and glia in brain regions outside the cerebral cortex including the bulbus medullae and anterior horn of the spinal cord (Cozzolino et al, 2008). Given these observations, it is possible that sPD and sALS share common pathogenic mechanisms and genes (GomesTrolin et al, 2002; Hu et al, 2017; Chen et al, 2018a,b; Yuan et al, 2018)
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