α-Synuclein Is Degraded by Both Autophagy and the Proteasome

Webb, Julie L.; Ravikumar, Brinda; Atkins, Jane T.; Skepper, Jeremy N.; Rubinsztein, David C.

doi:10.1074/jbc.m300227200

Cited by 1,343 publications

(1,159 citation statements)

References 38 publications

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“…We and others have previously demonstrated that a-synuclein aggregates were degraded via the autophagic-lysosomal degradation pathway. 12,13 Furthermore, it has been reported that the autophagy pathway generally plays a major role in clearance of cytoplasmic protein aggregates. 14 Therefore, we examined the effects of PLD1 inhibition on the cytoplasmic accumulation of a-synuclein.…”

Section: Resultsmentioning

confidence: 99%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

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Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, a-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of a-synuclein aggregates in autophagosomes. Neuronal toxicity caused by a-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of a-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

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Section: Resultsmentioning

confidence: 99%

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

et al. 2014

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“…α-Synuclein is one substrate and mutant forms of this protein appear to poison both the UPS and autophagy causing Parkinson's disease. [68][69][70] Another shared substrate is inhibitor kappa B alpha (IĸBα), the inhibitor of the transcription factor nuclear factor kappa B. 71 IĸBα appears to be degraded by the UPS and autophagy in different cellular compartments with different rates.…”

Section: Discussionmentioning

confidence: 99%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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“…167 Autophagy has been described for intracellular protein aggregates such as polyQ-huntingtin and ␣-synuclein aggregates, and also for tau. 168,169 Rapamycin inhibits mTOR (mammalian target of rapamycin), thereby promoting autophagy. In a Drosophila fruit fly model expressing wild-type or R406W mutant tau, treatment with rapamycin induced autophagic tau degradation and diminished tau-induced toxicity.…”

Section: Tau Clearancementioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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α-Synuclein Is Degraded by Both Autophagy and the Proteasome

Cited by 1,343 publications

References 38 publications

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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