Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Abstract

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

“…In fact, a dysfunctional membrane vesicle compartment started either in the retromer compartment of endosomes or within altered clathrin-mediated endocytosis [4,20] may be represented by engulfing multivesicular bodies (MVB). This may be added to or alternative to an early dysfunction of the autophagy machinery both at early and late stages, impeding the merging with lysosomes [30,50,[52][53][54]56,60,[116][117][118][119][120][121][122]. Still, in this scenario, a critical step involves the shuttling of the proteasome via p62 towards the nascent phagophore [123], where polyubiquitin chains interact with p62 to deliver misfolded proteins to segregated domains of degradation.…”

“…This may lead to engulfing multivesicular bodies (MVB). This may be added to or alternative to early dysfunction of the autophagy machinery (left part of the cartoon, and Figure 1) both at early and late stages, impeding the merging of the endosome/autophagosome system with lysosomes [30,50,[52][53][54]56,60,[116][117][118][119][120][121][122]. LRRK2: leucine-rich repeat kinase is altered in a genetic form of PD and it is involved in endolysosomal pathway.…”