CARGO RECOGNITION FAILURE IS RESPONSIBLE FOR INEFFICIENT AUTOPHAGY IN HUNTINGTON’S DISEASE

By Marta Martínez-Vicente, Z. Tallóczy, Esther Wong, Grace Tang, H. Koga, Susmita Kaushik, R. D. Vries, E. Arias, Spike Harris, D. Sulzer and 1 more. Nature Neuroscience, 2010

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Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, the main process responsible for bulk autophagic degradation, have been proposed to contribute to pathogenesis in Huntington's disease (HD), a genetic neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin protein. However, the precise mechanism behind macroautophagy malfunction in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from humans with HD, we have identified a primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo in HD cells. Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen. We propose that inefficient engulfment of cytosolic components by autophagosomes is responsible for their slower turnover, functional decay and accumulation inside HD cells.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7daf5c7dd0f54ef3b71c3f016f8e5fc212b518f1

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Citations in the corpus

Measuring in vivo mitophagy (2015, background): “Moreover, evidence suggest that in mouse models of Huntington’s disease there is impaired targeting of cytosolic and mitochondrial cargo to the autophagosome, leading to impaired removal of damaged proteins and organelles (Martinez-Vicente et al., 2010).”
Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits (2014, neutral): “…cultures (Figure S5B); (4) an accumulation of autophagy substrates, including p62 (Komatsu et al., 2007a), lipid droplets, and damaged mitochondria (Martinez-Vicente et al., 2010), in Tsc2+/ primary neuronal cultures (Figures S5B, S5C, S5D, and S5E); (5) accumulation of p62and Ub- positive…”
Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “PIP4Kg inhibition stimulates productive autophagy Numerous studies have shown that mHtt upregulates autophagy, but impairs incorporation of client proteins into autophagosomes (Cortes and La Spada, 2014; Ochaba et al., 2014; Martin et al., 2015; Martinez-Vicente et al., 2010; Tsvetkov et al., 2013).”
Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. (2011, background): “, 2009), as autophagy can remove protein aggregates (Bjørkøy et al., 2005; Filimonenko et al., 2010; Iwata et al., 2005; Martinez-Vicente et al., 2010; Ravikumar et al., 2004; Yamamoto et al., 2006).”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “…2012) Resveratrol (Wu et al., 2011) Isorhynchophylline (Lu et al., 2012) Huntington's disease Macroautophagy is debilitated to cargo recognition (Martinez-Vicente et al., 2010) Macroautophagy degrades Htt43Q (Carra et al., 2008) Macroautophagy is impaired in early stages of HD (Koga et al.,…”
Autophagy gone awry in neurodegenerative diseases (2010, neutral): “In fact, a paradoxical decrease in macroautophagy-mediated degradation, despite proper formation and clearance of autophagosomes, has recently been identified in different Huntington's disease model”