. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006 Jun 15;441(7095):880-4. PubMed.


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  1. 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).


    . Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22. PubMed.

    . Protein degradation and aging. Exp Gerontol. 2005 Aug-Sep;40(8-9):622-33. PubMed.

    . Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 2005 Oct 10;171(1):87-98. PubMed.

    . 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 Nixon
  2. 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.


    . Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell. 2000 Mar 31;101(1):57-66. PubMed.

    . 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 Kopito
  3. 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
    ubiquitinated 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.

    View all comments by Steven Finkbeiner

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