Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O'Kane CJ, Brown SD, Rubinsztein DC. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet. 2005 Jul;37(7):771-6. PubMed.
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New York University School of Medicine/Nathan Kline Institute
Rubinsztein and colleagues present strong evidence that macroautophagic turnover of proteins requires dynein, possibly to transport autophagosomes and lysosomes into juxtaposition for fusion and initiation of digestion. This role of dynein may be especially significant in neurons because of their long axons and dendrites, which often contain the bulk of the cell’s proteins and organelles. Peter Hollenbeck's group earlier showed in cultured neurons that immature autophagic vacuoles are actively formed within terminals and neurites, but their maturation to a digestive vacuole requires retrograde movement and fusion with hydrolase-containing vesicles closer to the cell body. These considerations are quite pertinent to Alzheimer disease where the very abundant dystrophic neurites in the brain have recently been shown to be filled mainly with autophagic vacuoles, in addition to lysosomes, suggesting that the retrograde transport of these organelles is interrupted (Nixon et al., 2005). The abundance of immature subtypes of autophagic vacuoles (e.g., autophagosomes) in the dystrophic neurite also implies that their fusion with lysosomes is impeded. Autophagic vacuoles contain the necessary components for Aβ generation, are enriched in γ-secretase activity, and are a major reservoir of intracellular Aβ (Yu et al., 2004, and J. Cell Biol., submitted). While normally, Aβ peptide may be degraded in lysosomes, the failure of autophagic vacuoles to mature to lysosomes creates conditions favorable for Aβ production and accumulation within these pre-lysosomal autophagic compartments.
The findings of the Rubinsztein group underscore the importance of macroautophagy for protecting neurons in the face of accumulating mutant proteins or, in other pathological situations, damaged organelles and proteins. Factors that impede the neuron's degradative pathways, including normal aging, increasingly are being recognized to have a powerful influence on the emergence of neurodegenerative diseases, ranging from developmental disorders to the late-age-onset proteinopathies (see ARF San Diego meeting report). Besides promoting accumulation of a given pathogenic protein, impaired macroautophagy almost certainly contributes to the degenerative process in other ways. Restoring or enhancing normal macroautophagy function in various neurodegenerative disorders may, therefore, be an attractive therapeutic avenue in the future.
References:
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22. PubMed.
Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol. 2004 Dec;36(12):2531-40. PubMed.
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