TY - JOUR
T1 - Transcriptional mutagenesis of α-synuclein caused by DNA oxidation in Parkinson’s disease pathogenesis
AU - Basu, Sambuddha
AU - Song, Minkyung
AU - Adams, Levi
AU - Jeong, Inhye
AU - Je, Goun
AU - Guhathakurta, Subhrangshu
AU - Jiang, Jennifer
AU - Boparai, Nikpreet
AU - Dai, Wei
AU - Cardozo-Pelaez, Fernando
AU - Tatulian, Suren A.
AU - Han, Kyu Young
AU - Elliott, Jordan
AU - Baum, Jean
AU - McLean, Pamela J.
AU - Dickson, Dennis W.
AU - Kim, Yoon Seong
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - 8-oxodG
KW - Alpha-synuclein aggregation
KW - Lewy bodies
KW - Parkinson’s disease
KW - Transcriptional mutagenesis
UR - http://www.scopus.com/inward/record.url?scp=85171876517&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85171876517&partnerID=8YFLogxK
U2 - 10.1007/s00401-023-02632-7
DO - 10.1007/s00401-023-02632-7
M3 - Article
C2 - 37740734
AN - SCOPUS:85171876517
SN - 0001-6322
VL - 146
SP - 685
EP - 705
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 5
ER -