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. Author manuscript; available in PMC: 2015 Apr 7.
Published in final edited form as: Nat Rev Mol Cell Biol. 2013 May;14(5):283–296. doi: 10.1038/nrm3565

Figure 3. Defective cellular clearance in neurodegenerative diseases.

Figure 3

Defective cellular clearance, leading to neurodegeneration, can result from two different mechanisms. First, loss-of-function mutations of genes involved in the lysosomal–-autophagic pathway (for example, ATP13A2, CATD, GBA1, PSEN1/2, VPS35, PINK, PARK, CHMP2B, RAB7, and WDR45) can affect cellular degradation and recycling processes. Second, gain-of-function mutations of aggregate-prone proteins (for example, SNCA, APP, HTT and MAPT) may lead to enhanced protein aggregation and engulfment of lysosomal–autophagic pathways. In addition, a global decrease of lysosomal–autophagy function has been observed during ageing and may contribute to an impairment of cellular clearance. Ultimately, and regardless of the mechanism involved, defective cellular clearance leads to the accumulation of neurotoxic proteins and neuronal cell death. (PD = Parkinson's disease; AD = Alzheimer's diseases; FTD = Fronto-Temporal Dementia; CMT2b = Charcot-Marie-Tooth type 2B; SENDA = Static Encephalopathy of Childhood with Neurodegeneration in Adulthood).