Quality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration

Abstract

The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be 'recycled.' Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.

Keywords: Gaucher disease; Parkinson's disease; autophagy; lysosomal storage disorders; lysosome; mitochondria; neurodegeneration; ubiquitin-proteasome system.

Figure 1

Cellular quality control pathways. Quality control pathways revolve around the autophagy pathway. Expansion of the isolation membrane is initiated by the Atg family of proteins. LC3-I is converted to LC3-II once conjugated to PE on the autophagosome membrane. Once damaged organelles and proteins are engulfed, the autophagosome fuses with the lysosome to form the autolysosome, which facilitates the degradation of the material. The UPS, CMA and mitophagy pathways degrade specific substrates. UPS, poly-ubiquitinated proteins; CMA, specific misfolded proteins; mitophagy, damaged mitochondria.