Open Collections

Wang, Rui

University of British Columbia

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Multiplication of SNCA, a gene encoding synaptic protein alpha-synuclein, leads to PD in a dosage-dependent manner. Although the clinical onset of PD generally occurs in late life, it is often preceded by a lengthy prodromal phase that coincides with midlife during which many non-motor and pathological signs of PD emerge. However, the precise role of excessive alpha-synuclein during midlife remains elusive. Although the canonical function of alpha-synuclein lies in its ability to coordinate synaptic transmission, recent studies suggest that it also plays an active role in epigenetic and transcriptomic regulation. Here, we investigated the epigenomic and transcriptomic landscape at both early and late stages of midlife in the hippocampus, a brain region linked to many cognitive impairments of PD, using a transgenic (TG) mouse model overexpressing human SNCA. When comparing TG mice against their age-matched wildtype (WT) counterparts, we observed a more pronounced influence of SNCA overexpression at late stage of midlife compared to early stage of midlife at both DNA methylation and transcriptional levels. SNCA overexpression also affected the isoform regulation of two distinct sets of genes at each of the two stages. Comparisons between mice at early midlife and mice at late midlife indicated that SNCA overexpression could affect the age-related progression of the epigenetic, transcriptional, and isoform regulatory dynamics of hundreds of genes during midlife. Characterization of the genes with a significant genotype or age effect implicated a wide array of molecular pathways and biological processes crucial for neurological functioning. These analyses further revealed specific molecular factors that may play a role in PD pathogenesis and are attractive targets for future validation studies. Taken together, this thesis demonstrated that SNCA overexpression triggered dysregulation of the hippocampal DNA methylome and transcriptome as well as alteration of the normal age progression of the hippocampal molecular landscape during midlife. This thesis further affirmed that the midlife is a crucial period for PD pathogenesis and underscored the importance of continued investigation into the role of excessive alpha-synuclein during this period.

Text

2024-05-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88392

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/