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Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci. 2008 Jul 2;28(27):6926-37. PubMed.
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Columbia University
Macroautophagy is a major mechanism for intracellular protein degradation. It begins with the engulfment of part of the cytoplasm, including intracellular organelles, by double membrane vacuolar structures, the autophagosomes; these structures then fuse with lysosomes, thus creating the autolysosomes in which the intracellular constituents are degraded. Observations in a number of neurodegenerative diseases, including Alzheimer disease, indicate that there is an extensive accumulation of autophagic vacuoles in affected tissues. Whether this represents an induction of the process of macroautophagy or an inhibition of the conversion of autophagosomes to mature lysosomes has been unclear.
Boland et al. now report, using a number of careful imaging and biochemical tools, that in cultured primary cortical neurons induction of macroautophagy through inhibition of mTOR leads to little accumulation of double-membrane LC3-II-positive autophagosomes, as these are rapidly converted to autolysosomes. In contrast, inhibition of lysosomal proteolysis or disruption of autophagosome-lysosome fusion led to abundant accumulation of double-membrane structures, most of them positive for LC3-II, indicating inhibition of macroautophagy-dependent degradation. These latter structures resemble those seen in Alzheimer disease brains, as well as in the brains of APP/PS1 Tg mice. The authors conclude that disruption of the process downstream of autophagosome formation, rather than induction of macroautophagy, is likely to be the main determinant leading to the marked vacuolar accumulation seen in AD.
The findings raise a number of questions:
First, what is the nature of the presumed defect in the “maturation” of the autophagic pathway? One possibility is that there is a defect in the fusion of autophagosomes into autolysosomes. This could be due to a general defect in axonal transport or to yet unknown properties specific to the budding vacuoles. Alternatively, the problem could lie within the lysosomes. Lysosomal dysfunction in cultured neurons, as shown convincingly in this study, but also in experimental animals or in humans, leads to accumulation of autophagic vacuoles. Lysosomal dysfunction as a primary event could also, in part, explain the defects in endocytosis observed early in the course of AD.
A second question, perhaps more important from the point of view of potential therapies, is whether this accumulation of autophagic vacuoles is beneficial or detrimental, and whether preventing or inducing it would be a good therapeutic strategy against neurodegeneration. The data from this paper indicate that the presence of autophagosomes in AD is a readout for a dysfunction of the downstream protein degradation pathway within lysosomes. Therefore, it would make little sense to further induce the macroautophagy pathway in this setting as a therapeutic strategy, especially since autophagic vacuoles aid Aβ production (Yu et al., 2005). It would be better, in fact, to find ways to boost either the fusion event or lysosomal function in general.
Of course, the AD disease process could have additional effects on the autophagic/lysosomal pathway, as the authors themselves recognize. In fact, a recent manuscript (Pickford et al., 2008) has suggested that an early event in AD is the reduction of beclin-1, a protein that promotes macroautophagy; modulation of beclin-1 influenced the phenotype of APP transgenic mice, suggesting that the reduction of beclin-1, and the resultant reduction in macroautophagic degradation, observed in AD could have detrimental effects. Although seemingly contradictory, these reports both highlight the fact that there is dysfunction of the autophagic/lysosomal pathway in AD, perhaps at various levels. Lysosomal dysfunction with marked induction of autophagic vacuoles has been reported previously by us in the setting of aberrant α-synuclein expression in a PC12 cell model (Stefanis et al., 2001). Therefore, alterations of this pathway may play a significant role in various neurodegenerative conditions and could represent therapeutic targets.
References:
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.
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.
Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA. Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci. 2001 Dec 15;21(24):9549-60. PubMed.
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