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Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006 Jun 15;441(7095):885-9. PubMed.
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New York University School of Medicine/Nathan Kline Institute
The extreme scarcity of autophagic vacuoles in normal brain and their appearance in states of disease have previously led many to assume that autophagy in neurons is mainly an inducible process. Autophagy is solely responsible for organelle turnover, however, and the large cytoplasmic mass of neurons would suggest, therefore, that autophagy might have a significant constitutive component. The two papers by Komatsu et al. and Hara et al. have now provided elegant and definitive evidence in neurons for constitutive autophagy and have demonstrated that it is required for neuron survival. In fact, the results imply that the brain may actually be one of the tissues most vulnerable to a possible impairment of autophagy. These findings, therefore, offer insight into why neurons are preferentially victimized in diseases that disrupt the lysosomal system, even when the disease is a systemic one.
This new evidence for actively ongoing autophagy in neurons, which normally proceeds in the absence of readily detectable morphological intermediates (i.e., autophagic vacuoles), indicates that this process in healthy neurons is exceptionally efficient. Another implication from these observations is that autophagic vacuole accumulation in neurodegenerative disease states may signify a failing autophagy system, rather than simply an activation of autophagy as is frequently proposed. The findings are highly relevant to Alzheimer disease (AD) where autophagic function is impaired as evidenced by a massive build-up of autophagy intermediates especially within dystrophic dendrites of affected neurons. This indicates that the usually efficient progression of autophagosomes to lysosomes is impeded (Nixon et al. 2005). Autophagosome-lysosome fusion is already known to be slowed by normal cell aging (Martinez-Vincente et al. 2005) and additional risk factors for AD are likely to be found to impair autophagy. Autophagic vacuoles are highly enriched in γ-secretase and actively generate Aβ during autophagy (Yu et al., 2005). Although normally most of the generated Aβ would be degraded within lysosomes, in AD and transgenic AD models, the marked build-up of autophagic intermediates within an impaired autophagy pathway is a significant source and intracellular reservoir of Aβ (Yu et al., 2005). The two new papers, in the context of these other recent observations, therefore, support potential links between autophagic failure and neurodegeneration, amyloidogenesis, and possibly the intracellular accumulation of other disease-related proteins in AD. Therapeutic strategies based on facilitating efficient autophagy show glimpses of promise in neurodegenerative disease models (e.g., Ravikumar et al., 2004).
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.
Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol. 2005 Aug-Sep;40(8-9):622-33. PubMed.
Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 2005 Oct 10;171(1):87-98. PubMed.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004 Jun;36(6):585-95. PubMed.
View all comments by Ralph NixonStanford University
The recent papers by the Mizushima and Tanaka labs provide compelling support of a role for autophagy in the constitutive turnover of cellular material and the importance of this process in maintenance of neuronal health. However, the conclusion that autophagy has no role in the clearance of inclusion bodies is premature. There is now strong evidence from conditional models of polyglutamine disease (e.g., Yamamoto et al., 2000 and Zu et al., 2004) to indicate that neurons can eliminate inclusion bodies and can recover from the toxic effects of aggregated protein—once expression is turned off. While there is no direct evidence yet that autophagy is required for this process, the Mizushima and Tanaka groups are now in an excellent position to test this hypothesis.
References:
Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell. 2000 Mar 31;101(1):57-66. PubMed.
Zu T, Duvick LA, Kaytor MD, Berlinger MS, Zoghbi HY, Clark HB, Orr HT. Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J Neurosci. 2004 Oct 6;24(40):8853-61. PubMed.
View all comments by Ron KopitoUniversity of California, San Francisco
This pair of papers shows that disruption of the autophagy pathway
through deletion of the genes that encode critical components of the
pathway (i.e., either Atg5 or Atg7) within neurons leads to
behavioral abnormalities, neurodegeneration, and inclusion formation.
The papers are interesting for several reasons.
First, although features of autophagy are known to be involved in
normal protein turnover and may be part of a coping response to
nutrient deficiency, it also is believed to be a programmed cell death
pathway. Thus, it was unclear whether disruption of this pathway
would lead to greater cell death because of impaired protein turnover
or greater cell survival as seen when another cell death pathway,
apoptosis, is disrupted. The fact that abnormal protein accumulation
and greater cell death is seen indicates that autophagy plays a
critical role in normal protein turnover in mammalian systems.
Second, ubiquitin immunoreactive inclusions were found in both Atg5-
and Atg7-deficient mice, despite the fact that these mice were not
known to otherwise harbor a genetic mutation producing
aggregation-prone proteins. Although not shown in these papers,
inclusion formation can be observed following inhibition of the
proteasome, the other major protein degradation pathway. One of the
two groups examined proteasome function in the Atg7-deficient mice
and found no proteasome impairment (although it would have been interesting to examine proteasome function in vivo). Taken at face value, these results add
further support to the notion that inclusion formation is a
downstream cellular response to the accumulation of proteins that are
otherwise destined for degradation. Notably, the paper by Tanaka and
colleagues found that the accumulation of "diffuse" cytosolic
ubiquitin immunoreactivity occurred first, before inclusion
formation, and was a more consistent phenotype of autophagy
disruption than inclusion formation.
Although it is generally assumed that the proteins that are
View all comments by Steven Finkbeinerubiquitinated and accumulate in inclusion bodies are misfolded and
possibly non-functional, the finding here raises the provocative
possibility that inclusions may form, in part, from normal proteins
that accumulate when degradation is impaired. In such a scenario,
pathogenesis might arise from having too much of a good thing.
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