Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders

• Main Authors: Scott Ugras, Malcolm J. Daniels, Hossein Fazelinia, Neal S. Gould, Anastasia K. Yocum, Kelvin C. Luk, Esteban Luna, Hua Ding, Chris McKennan, Steven Seeholzer, Dan Martinez, Perry Evans, Daniel Brown, John E. Duda, Harry Ischiropoulos
• Format: Article
• Language: English
• Published: Elsevier 2018-05-01
• Series: EBioMedicine
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352396418301622

Accumulation of aggregated α-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 α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-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 α-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. Keywords: Neurodegeneration, Parkinson's disease, Dopaminergic neurons, Immunoproteasome, Proteostasis