Protein clearance mechanisms of alpha-synuclein and amyloid-Beta in lewy body disorders

Abstract

Protein clearance is critical for the maintenance of the integrity of neuronal cells, and there is accumulating evidence that in most-if not all-neurodegenerative disorders, impaired protein clearance fundamentally contributes to functional and structural alterations eventually leading to clinical symptoms. Dysfunction of protein clearance leads to intra- and extraneuronal accumulation of misfolded proteins and aggregates. The pathological hallmark of Lewy body disorders (LBDs) is the abnormal accumulation of misfolded proteins such as alpha-synuclein (Asyn) and amyloid-beta (Abeta) in a specific subset of neurons, which in turn has been related to deficits in protein clearance. In this paper we will highlight common intraneuronal (including autophagy and unfolded protein stress response) and extraneuronal (including interaction of neurons with astrocytes and microglia, phagocytic clearance, autoimmunity, cerebrospinal fluid transport, and transport across the blood-brain barrier) protein clearance mechanisms, which may be altered across the spectrum of LBDs. A better understanding of the pathways underlying protein clearance-in particular of Asyn and Abeta-in LBDs may result in the identification of novel biomarkers for disease onset and progression and of new therapeutic targets.

Figure 1

Intra- and extraneuronal mechanisms of protein clearance. The main intracellular pathways for the degradation and recycling of proteins are the ubiquitin/proteasome system (UPS) and the autophagy-lysosomal pathway (microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA)). Extracellular clearance pathways include interaction of neurons with astro- and microglia, and with infiltrating macrophages, autoantibodies, and protein transport from the parenchyma to the cerebrospinal fluid and across the blood-brain barrier. The engulfment of misfolded proteins by astro- and microglia triggers the release of proinflammatory cytokines and chemokines as well as reactive oxygen/nitrogen species, which may, under pathological conditions, further promote neuronal dysfunction and degeneration.