Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond.
Selective degeneration and death of one or more classes of neurons is the defining feature of human neurodegenerative disease. Although traditionally viewed as diseases mainly affecting the most vulnerable neurons, in most instances of inherited disease the causative genes are widely-usually ubiquitously-expressed. Focusing on amyotrophic lateral sclerosis (ALS), especially disease caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1), we review here the evidence that it is the convergence of damage developed within multiple cell types, including within neighboring nonneuronal supporting cells, which is crucial to neuronal dysfunction. Damage to a specific set of key partner cells as well as to vulnerable neurons may account for the selective susceptibility of neuronal subtypes in many human neurodegenerative diseases, including Huntington's disease (HD), Parkinson's disease (PD), prion disease, the spinal cerebellar ataxias (SCAs), and Alzheimer's disease (AD).
Ilieva
Hristelina
H
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Polymenidou
Magdalini
M
Cleveland
Don W
DW
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D001370:Axonal Transport; D002196:Capillaries / Q000201:enzymology / Q000473:pathology; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology
C000606290:SOD1 protein, human; D013481:Superoxides; D018698:Glutamic Acid; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1