title: Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria.
abstract: Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson's disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C > G (Pro143Ala) and c.906 +3 G > A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5-2.8, P = 0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD.
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Lin
authors.forename: Meng-Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.forename: Chun-Hwei
authors.initials: CH
authors.lastname: Tai
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
mesh_terms: D000328:Adult; D017668:Age of Onset; D017209:Apoptosis / Q000235:genetics; D044466:Asian People; D016022:Case-Control Studies; D059290:Dopaminergic Neurons / Q000473:pathology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017421:Sequence Analysis / Q000379:methods; D017422:Sequence Analysis, DNA / Q000379:methods; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2