期刊
EBIOMEDICINE
卷 31, 期 -, 页码 307-319出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2018.05.007
关键词
Neurodegeneration; Parkinson's disease; Dopaminergic neurons; Immunoproteasome; Proteostasis
资金
- National Institute of Health [NINDS NS088322, U54 HD 086984, NIA-AG13966]
Accumulation of aggregated alpha-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how alpha-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of alpha-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades alpha-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. (C) 2018 The Authors. Published by Elsevier B.V.
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