Alpha-synuclein's degradation in vivo: opening a new (cranial) window on the roles of degradation pathways in Parkinson disease

Abstract

Progressive accumulation of α-synuclein is key to the pathology of many neurodegenerative diseases, including Parkinson disease and dementia with Lewy bodies. Increased intracellular levels of α-synuclein may be caused by enhanced expression or alterations in protein degradation pathways. Here we review our recent study showing that the ubiquitin-proteasome system and the autophagy-lysosomal pathway are differentially involved in α-synuclein's degradation in vivo. We discuss the key findings obtained with our novel in vivo approach and also present a model for the progression of protein aggregation and dysfunctional degradation in Parkinson disease.

Figure 1

Proposed model for the role of protein degradation pathways in Parkinson disease. Primary dysfunction of protein degradation may lead to excess levels of α-synuclein and the formation of pathologically modified species that overwhelm the capacity of chaperones, the ubiquitin-proteasome system (UPS) and chaperone-mediated autophagy (CMA). In the next stage, macroautophagy is induced and temporary homeostasis is achieved before this balance finally tilts. Entering the late disease stage, α-synuclein inhibits macroautophagy and lysosomal degradation. Uncontrolled accumulation produces oligomeric species that cause neuronal dysfunction and degeneration. At the same time, excess levels of α-synuclein might trigger α-synuclein secretion, thus potentially contributing to a spread of the pathology.