Autophagy-lysosomal pathway in neurodegeneration

Abstract

Autophagy-Lysosomal Pathway (ALP) dysfunction has emerged as a prominent mechanism underlying neurodegenerative disease. Given its central role in facilitating cellular clearance of misfolded proteins, damaged organelles and other cellular debris, the ALP is vital for cellular health and survival. In mature neurons, whose post-mitotic state renders them unable to dilute such materials through cell division, this waste removal pathway takes on an even greater importance. It is therefore unsurprising that ALP dysfunction is increasingly implicated in the context of age-associated neurodegenerative disease, where impaired proteostasis and pathological protein aggregation are common hallmarks. The focus of this review is how dysregulation of ALP-associated processes, including autophagic flux, chaperone-mediated autophagy, endolysosomal trafficking, lysosomal pH and ion balance, and lysosomal metabolic signaling, is implicated in both the pathogenesis and progression of neurodegenerative diseases, with an emphasis on Alzheimer’s disease and Parkinson’s disease. A more detailed understanding of how these processes, both independently and cooperatively, contribute to the development and progression of neurodegenerative disease will improve our understanding of these debilitating disorders and inform the development of ALP-targeted therapeutic strategies.