Janus-faced autophagy: a dual role of cellular self-eating in neurodegeneration?
Autophagy is a highly regulated cellular pathway used by eukaryotic cells to consume parts of their constituents during development or starvation. It is associated with extensive rearrangements of intracellular membranes, and involves the cooperation of many gene products in the regulation and execution phase by largely unknown mechanisms. Recent results strongly indicate the role of autophagy in the degradation of damaged macromolecules, in particular misfolded, aberrant proteins, and in organelle turnover; in mutant mice with reduced autophagy, accumulation of abnormal cytosolic proteins as inclusion bodies and massive cell loss occur similarly to human neurodegenerative disorders. Thus, autophagy seems to prevent neurons from undergoing protein aggregation-induced degeneration. In contrast, we have shown that inactivation of genes involved in autophagosome formation suppresses neuronal demise induced by various hyperactivating ion channel mutations or by neurotoxins in the nematode Caenorhabditis elegans. These results raise the possibility that autophagy may also contribute to excitotoxic necrotic-like cell death. This way, autophagic degradation of cytoplasmic materials might have a dual role in the survival of neurons. Depending on the actual cellular milieu and insulting factor, it can act both as a protector and contributor to neuronal damage.
Vellai
Tibor
T
Department of Genetics, Eötvös Loránd University, Budapest, Hungary. vellai@falco.elte.hu
Tóth
Márton L
ML
Kovács
Attila L
AL
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D017238:Genes, Helminth; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000502:physiology; D008959:Models, Neurological; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*
D007473:Ion Channels