The role of autophagy in neurodegenerative disease

Nixon, Ralph A.

doi:10.1038/nm.3232

Cited by 1,754 publications

(1,624 citation statements)

References 229 publications

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“…This inability to adapt the autophagic response to stressors would be particularly worrisome in the context of a chronic disease in the aging brain where a failure of autophagy might trigger faster disease progression. In fact, defective macroautophagy has been extensively reported in FTD and other tauopathies (Nixon, 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Aberrant proteins are normally handled by the proteostasis networks responsible for maintaining protein quality control (Kaushik & Cuervo, 2015). Among the proteolytic systems of these networks, autophagy or protein breakdown in lysosomes has proven effective in maintenance of a healthy proteome (Nixon, 2013). However, numerous evidences suggest that protein variants shown to contribute to the pathogenesis of neurodegenerative disorders may fail to undergo degradation by autophagy and accumulate intracellularly resulting in cell toxicity and often cell death (Nixon, 2013; Menzies et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Among the proteolytic systems of these networks, autophagy or protein breakdown in lysosomes has proven effective in maintenance of a healthy proteome (Nixon, 2013). However, numerous evidences suggest that protein variants shown to contribute to the pathogenesis of neurodegenerative disorders may fail to undergo degradation by autophagy and accumulate intracellularly resulting in cell toxicity and often cell death (Nixon, 2013; Menzies et al ., 2015). Defective autophagy is sometimes a consequence of modifications on the pathogenic proteins that prevent their autophagic removal, whereas in other instances, pathogenic proteins directly impair the autophagic systems (Wong & Cuervo, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…The observed failure of fusion of autophagosomes with lysosomes may also be relevant to the recently appreciated association between GD and parkinsonism (Sidransky et al ., 2009; Siebert et al ., 2014). In fact, there is literature suggesting that impaired autophagy and lysosomal dysfunction in neurodegenerative disorders can result in a failure to clear accumulated protein aggregates (Lynch‐Day et al ., 2012; Nixon, 2013). Lysosomal dysfunction is also an important factor in the aging process.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

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“…Concerning autophagy‐dependent mechanism, activation of mTOR inhibits the kinase activity of ULK1 and thus blocks the initial formation of phagopores (Min et al., 2017). The downregulated autophagy subsequently results in reduced clearance of Aβ, elevated Aβ deposition, and eventually formation of Aβ plaques (Nixon, 2013). Moreover, the insufficient autophagy could also lower the clearance of misfolded tau proteins, leading to the accumulation of tau aggregates in the cytoplasm of neurons (Li et al., 2017).…”

Section: The Important Role Of Protein Synthesis Pathways In Cancer Amentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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The role of autophagy in neurodegenerative disease

Cited by 1,754 publications

References 229 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

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