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TitleTranscriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson's disease pathogenesis.
Journal, issue, pagesActa Neuropathol, Vol. 146, Issue 5, Page 685-705, Year 2023
Publish dateSep 23, 2023
AuthorsSambuddha Basu / Minkyung Song / Levi Adams / Inhye Jeong / Goun Je / Subhrangshu Guhathakurta / Jennifer Jiang / Nikpreet Boparai / Wei Dai / Fernando Cardozo-Pelaez / Suren A Tatulian / Kyu Young Han / Jordan Elliott / Jean Baum / Pamela J McLean / Dennis W Dickson / Yoon-Seong Kim /
PubMed AbstractOxidative stress plays an essential role in the development of Parkinson's disease (PD). 8-oxo-7,8-dihydroguanine (8-oxodG, oxidized guanine) is the most abundant oxidative stress-mediated DNA lesion. ...Oxidative stress plays an essential role in the development of Parkinson's disease (PD). 8-oxo-7,8-dihydroguanine (8-oxodG, oxidized guanine) is the most abundant oxidative stress-mediated DNA lesion. However, its contributing role in underlying PD pathogenesis remains unknown. In this study, we hypothesized that 8-oxodG can generate novel α-synuclein (α-SYN) mutants 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 analysis 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 compared to WT α-SYN as shown in mouse primary cortical cultures and AAV-mediated overexpression in the substantia nigra of C57BL/6 J mice. To our knowledge, this is the first report describing the possible contribution of TM-generated mutations of α-SYN to LB formation and PD pathogenesis.
External linksActa Neuropathol / PubMed:37740734 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-28752: Cryo-electron tomography of wild type a-synuclein preformed fibrils
Method: EM (tomography)

EMDB-28753: Cryo-electron tomography of S42Y a-synuclein preformed fibrils
Method: EM (tomography)

Source
  • Escherichia coli BL21(DE3) (bacteria)

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