Transcriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson’s disease pathogenesis

In this study, we hypothesized that 8-oxodG can generate novel α-synuclein (α-SYN) mutant s with altered pathologic aggregation through a phenomenon called transcriptional mutagenesis (TM). We observed a significantly higher accumulation of 8-oxodG in the midbrain genomic DNA from PD patients compared to age-matched controls, both globally and region specifically to α-SYN. In-silico ana lysis predicted that forty-three amino acid positions can contribute to TM-derived α-SYN mutation. Here, we report a significantly higher load of TM-derived α-SYN mutants from the midbrain of PD patients compared to controls using a sensitive PCR-based technique. We found a novel Serine42Tyrosine (S42Y) α-SYN as the most frequently detected TM mutant, which incidentally had the highest predicted aggregation score amongst all TM variants. Immunohistochemistry of midbrain sections from PD patients using a newly characterized antibody for S42Y identified S42Y-laden Lewy bodies (LB). We further demonstrated that the S42Y TM variant significantly accelerates WT α-SYN aggregation by cell and recombinant protein-based assays. Cryo-electron tomography revealed that S42Y exhibits considerable conformational heterogeneity compared to WT fibrils. Moreover, S42Y exhibited higher neurotoxicity co mpared to WT α-SYN as shown in mouse primary cortical cultures and AAV-mediated overexpression in thesubstantia nigra of C57BL/6  J mice. To our knowledge, this is the first report describing the possible...
Source: Acta Neuropathologica - Category: Neurology Source Type: research