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...  Read more

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; 64:113-122. Abstract

Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol. 2005 Aug-Sep;40(8-9):622-33. Abstract

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, Naslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy, a novel amyloid-beta (Abeta) peptide-generating pathway activated in Alzheimer's disease. JCB 2005; 171:87-98. Abstract

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. Epub 2004 May 16. Abstract

View all comments by Ralph Nixon

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.

View all comments by Ron Kopito

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...  Read more

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

The results in Jaeger et al. reinforce previous work from their lab (Pickford et al., 2008) showing that autophagy is a significant APP turnover pathway that can be strongly upregulated in cells. During autophagy induction, APP levels decreased somewhat more than Aβ levels, consistent with earlier data that Aβ is generated during autophagy and that efficient lysosomal proteolysis is needed to prevent the intracellular buildup of Aβ in autophagic vacuoles and lysosomes seen in AD. The authors also show that the block in autophagosome clearance in AD and AD mouse models can be exacerbated by beclin deficiency. This may be due to the impairment of early autophagy steps of autophagosome formation, which require beclin, as proposed in the paper, and it could also reflect interference with beclin-dependent late endosome functions, disturbances of which are known to disrupt amphisome formation and clearance through autophagy (1). Interestingly, the resultant buildup of APP and β-CTF in endosomal-related compartments is reminiscent of the...  Read more

The results in Jaeger et al. reinforce previous work from their lab (Pickford et al., 2008) showing that autophagy is a significant APP turnover pathway that can be strongly upregulated in cells. During autophagy induction, APP levels decreased somewhat more than Aβ levels, consistent with earlier data that Aβ is generated during autophagy and that efficient lysosomal proteolysis is needed to prevent the intracellular buildup of Aβ in autophagic vacuoles and lysosomes seen in AD. The authors also show that the block in autophagosome clearance in AD and AD mouse models can be exacerbated by beclin deficiency. This may be due to the impairment of early autophagy steps of autophagosome formation, which require beclin, as proposed in the paper, and it could also reflect interference with beclin-dependent late endosome functions, disturbances of which are known to disrupt amphisome formation and clearance through autophagy (1). Interestingly, the resultant buildup of APP and β-CTF in endosomal-related compartments is reminiscent of the conditions that develop in Down syndrome, where it has been shown that APP duplication, through elevations of β-CTF, accelerates endocytosis (2). This creates more substrate traffic to lysosomes, interferes with endosome functions (2,3), and we suspect, also impairs autophagic turnover. These new investigations add to mounting evidence that disruption of lysosomal clearance mechanisms may be a critical factor in AD pathogenesis.

References:
1. Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol. 2007 Nov 5;179(3):485-500. Abstract

2. Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA. Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1630-5. Abstract

3. Cataldo AM, Mathews PM, Boiteau AB, Hassinger LC, Peterhoff CM, Jiang Y, Mullaney K, Neve RL, Gruenberg J, Nixon RA. Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am J Pathol. 2008 Aug;173(2):370-84. Abstract

View all comments by Ralph Nixon