Abstract
Synucleinopathies are a family of neurodegenerative disorders that comprises Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Each of these disorders is characterized by devastating motor, cognitive, and autonomic consequences. Current treatments for synucleinopathies are not curative and are limited to improvement of quality of life for affected individuals. Although the underlying causes of these diseases are unknown, a shared pathological hallmark is the presence of proteinaceous inclusions containing the α-synuclein (α-syn) protein in brain tissue. In the past few years, it has been proposed that these inclusions arise from the self-templated, prion-like spreading of misfolded and aggregated forms of α-syn throughout the brain, leading to neuronal dysfunction and death. In this review, we describe how impaired protein homeostasis is a prominent factor in the α-syn aggregation cascade, with alterations in protein quality control (PQC) pathways observed in the brains of patients. We discuss how PQC modulates α-syn accumulation, misfolding and aggregation primarily through chaperoning activity, proteasomal degradation, and lysosome-mediated degradation. Finally, we provide an overview of experimental data indicating that targeting PQC pathways is a promising avenue to explore in the design of novel neuroprotective approaches that could impede the spreading of α-syn pathology and thus provide a curative treatment for synucleinopathies.
Highlights
Maintaining protein homeostasis is essential for normal cellular function and viability
Protein Quality Control in Synucleinopathies that are irreversibly misfolded, damaged, or are no longer required by the cell. We focus on these aspects of protein quality control (PQC); with other PQC pathways reviewed elsewhere (Wolff et al, 2014; Dubnikov et al, 2017)
heat shock protein (Hsp) or heat shock chaperones (Hscs) are a prominent group of chaperones and they can be found in the ER, mitochondria, cytoplasm or extracellular space (Hartl et al, 2011; Wyatt et al, 2013)
Summary
Maintaining protein homeostasis is essential for normal cellular function and viability. (4) Overexpression of the transcription factor NRF2 activates both macroautophagy and CMA and stimulates the lysosomal degradation of misfolded α-syn. Stabilizes client proteins by preventing Hsp70-mediated UPS targeting; favors fibrillization of α-syn, shifting the aggregation eqilibrium away from early toxic soluble misfolded species
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