Researchers here review some of the evidence for a two-way relationship between the age-related failure of autophagy and the accumulation of harmful protein aggregates that characterizes many neurodegenerative conditions. Autophagy is a collection of cellular maintenance processes responsible for recycling unwanted or damaged proteins and structures, but isn't just the case that failure of autophagy can lead to the spread of protein aggregates. It is also possible that the presence of these aggregates can cause a loss of autophagy, implying a vicious cycle of progression of these age-related conditions.
A hallmark of many neurodegenerative diseases is the progressive formation of insoluble protein aggregates. There are two main factors that cause protein aggregation in neurodegenerative diseases: mutations in genes encoding aggregate-prone proteins and the decline of cellular degradation functions, in particular of the autophagy-lysosomal pathway (ALP).
ALP is a major process for degrading intracellular macromolecules and generating energy or building blocks to make other macromolecules. ALP relies on the engulfment of cargos to be degraded (macromolecules or damaged organelles) in double-membrane vesicles (autophagosomes), which, therefore, fuse with endosomes/lysosomes to form autolysosomes, where autophagosome contents are degraded by lysosomal enzymes. ALP plays a key role in protein homeostasis and in the clearance of protein aggregates (processes that are particularly important in non-dividing neurons).
Mounting evidence also shows that protein aggregation itself may affect ALP, thus generating a vicious cycle, which boost protein aggregation and toxicity. Different works have shown that the aggregated forms of α-synuclein can bind the lysosome, thus impairing the chaperone-mediated autophagy or inducing lysosomal rupture. The interplay between protein aggregation and ALP dysfunction is crucial in driving neurodegenerative processes in a number of neurological conditions.
Link: https://doi.org/10.3...nmol.2020.00037
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