Neurodegenerative lysosomal disorders: a continuum from development to late age.
Neuronal survival requires continuous lysosomal turnover of cellular constituents delivered by autophagy and endocytosis. Primary lysosomal dysfunction in inherited congenital "lysosomal storage" disorders is well known to cause severe neurodegenerative phenotypes associated with accumulations of lysosomes and autophagic vacuoles (AVs). Recently, the number of inherited adult-onset neurodegenerative diseases caused by proteins that regulate protein sorting and degradation within the endocytic and autophagic pathways has grown considerably. In this Perspective, we classify a group of neurodegenerative diseases across the lifespan as disorders of lysosomal function, which feature extensive autophagic-endocytic-lysosomal neuropathology and may share mechanisms of neurodegeneration related to degradative failure and lysosomal destabilization. We highlight Alzheimer's disease as a disease within this group and discuss how each of the genes and other risk factors promoting this disease contribute to progressive lysosomal dysfunction and neuronal cell death.
Nixon
Ralph A
RA
Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York 10962, USA. nixon@nki.rfmh.org
Yang
Dun-Sheng
DS
Lee
Ju-Hyun
JH
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*