Neurodegenerative lysosomal disorders: a continuum from development to late age

Autophagy. 2008 Jul;4(5):590-9. doi: 10.4161/auto.6259. Epub 2008 May 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology*
  • Aging / physiology
  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Autophagy / genetics
  • Autophagy / physiology
  • Humans
  • Lysosomal Storage Diseases / etiology*
  • Lysosomal Storage Diseases / genetics
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / pathology*
  • Lysosomes / enzymology
  • Lysosomes / genetics
  • Lysosomes / pathology*
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology*