Details

Autor(en) / Beteiligte

• Basu, Sambuddha
• Song, Minkyung
• Adams, Levi
• Jeong, Inhye
• Je, Goun
• Guhathakurta, Subhrangshu
• Jiang, Jennifer
• Boparai, Nikpreet
• Dai, Wei
• Cardozo-Pelaez, Fernando
• Tatulian, Suren A.
• Han, Kyu Young
• Elliott, Jordan
• Baum, Jean
• McLean, Pamela J.
• Dickson, Dennis W.
• Kim, Yoon-Seong

Titel

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

Ist Teil von

• Acta neuropathologica, 2023-11, Vol.146 (5), p.685-705

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.