Involvement of macroautophagy in the dissolution of neuronal inclusions

Rideout, Hardy J.; Lang-Rollin, Isabelle; Stefanis, Leonidas

doi:10.1016/j.biocel.2004.05.008

Cited by 156 publications

(127 citation statements)

References 34 publications

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“…[77][78][79] In several aggregating-protein disease models, autophagy is implicated in degrading or preventing the formation of protein inclusions. 20,[80][81][82][83] We do not have evidence that the intracellular Aβ-deposits observed in our model 32 are the targeted cargo of autophagosomes (at least not in their entirety) because they are generally much larger than even the largest observed autophagosomes. This interpretation agrees with reports that polyglutamine and polyalanine protein inclusions are larger than autophagosomes and thus are incompatible as their cargo.…”

Section: Do Not Distributementioning

confidence: 65%

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Florez-McClure¹,

Hohsfield²,

Fonte³

et al. 2007

Autophagy

123

104

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Autophagy is a conserved membrane trafficking pathway that mediates the delivery of cytoplasmic substrates to the lysosome for degradation. Impaired autophagic function is implicated in the pathology of various neurodegenerative diseases. We have generated transgenic C. elegans that express human β-amyloid peptide (Aβ) in order to examine the mechanism(s) of Aβ-toxicity. In this model, Aβ expression causes autophagosome accumulation, thereby mimicking a pathology found in brains of Alzheimer's disease patients. Furthermore, we demonstrate that decreased insulin-receptor signaling [using the daf-2(e1370) mutation] suppresses Aβ-induced paralysis by a mechanism that requires autophagy. Surprisingly, the daf-2 mutation also decreases Aβ-induced autophagosome accumulation. These observations can be explained by a model in which decreased insulin-receptor signaling promotes the maturation of autophagosomes into degradative autolysosomes, whereas Aβ impairs this process. Consistent with this model, we find that RNAi-mediated knock-down of lysosomal components results in enhanced Aβ-toxicity and autophagosome accumulation. Also, Aβ; daf-2(e1370) nematodes contain more lysosomes than either Aβ or control strains. Finally, we demonstrate that decreased insulin-receptor signaling promotes the autophagic degradation of Aβ.

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Section: Do Not Distributementioning

confidence: 65%

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Florez-McClure¹,

Hohsfield²,

Fonte³

et al. 2007

Autophagy

123

104

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“…Inhibition of both the proteasome and autophagy increased the levels of ␣-SYN in PC12 cells with ␣-SYN in autophagic vacuoles and lysosomes (85). In cultured cortical neurons, proteasome inhibition led to activation of macroautophagy and the lysosomal pathway (86). In cultured neuronal cells, ␣-SYN oligomers, but not mature fibrillar inclusions, were cleared by the lysosomal pathway (87).…”

Section: ␣-Syn a Major Component Of Lbmentioning

confidence: 99%

Lewy bodies

Shults

2006

Proc. Natl. Acad. Sci. U.S.A.

402

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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“…Induction of autophagy has been reported to attenuate the toxicity induced by proteasome inhibition [59], suggesting that induction of autophagy is protective by removing protein aggregates. Many studies have found that inhibition of the UPS causes upregulation of autophagy, and that suppression of autophagy leads to accumulation of polyubiqutinated protein aggregates [60][61][62][63][64]. Also, rapamycin treatment to activate autophagy increased clearance of aggregate-prone proteins and reduced the appearance of protein aggregates in vitro and in vivo [39,65,66].…”

Section: Mechanisms Of Cardioprotectionmentioning

confidence: 99%

Recycle or die: The role of autophagy in cardioprotection

Gustafsson

Gottlieb

2008

Journal of Molecular and Cellular Cardiology

172

153

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Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggragates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy is essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.

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Involvement of macroautophagy in the dissolution of neuronal inclusions

Cited by 156 publications

References 34 publications

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

Lewy bodies

Recycle or die: The role of autophagy in cardioprotection

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