Rab1A Over-Expression Prevents Golgi Apparatus Fragmentation and Partially Corrects Motor Deficits in an Alpha-Synuclein Based Rat Model of Parkinson's Disease

Coune, Philippe Guillaume; Bensadoun, Jean-Charles; Aebischer, Patrick; Schneider, Bernard L.

doi:10.3233/jpd-2011-11058

Cited by 60 publications

(69 citation statements)

References 41 publications

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“…The Rab proteins, small GTPases involved in membrane trafficking, play pivotal roles in the maintenance of the Golgi morphology [56]. For example, the suppression of Rab1A involved in the ER-to-Golgi trafficking, was shown to induce a fragmentation of the Golgi whereas its overexpression had the opposite effect [41, 57]. Firstly, we examined the distribution of Rab1A in primary cortical neurons by transfecting them with GFP-Rab1A construct (Fig 6A).…”

Section: Resultsmentioning

confidence: 99%

Tau secretion is correlated to an increase of Golgi dynamics

2017

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Tau protein can be released by neurons, an event linked to the propagation of Tau pathology in Alzheimer’disease (AD). Neuronal hyperexcitability was shown to significantly increase Tau release by neurons. We confirmed this in the present study. In a previous study, it was demonstrated that hyperexcitability induces Golgi apparatus dynamics resulting in its fragmentation. Our present results revealed that the increase of Tau secretion upon hyperexcitability could be significantly reduced by preventing Golgi dynamics through the inactivation of cdk5. We then verified whether a Golgi fragmentation not induced by hyperexcitability could also increase Tau secretion. The suppression of Rab1A, Rab GTPase associated with the Golgi membranes, known to induce a Golgi fragmentation increased Tau secretion by both neurons and HeLa cells. Although it remains to be demonstrated whether the Golgi is directly involved in Tau secretion, the present results demonstrate that its dynamics are correlated to a modulation of Tau secretion.

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Section: Resultsmentioning

confidence: 99%

Tau secretion is correlated to an increase of Golgi dynamics

2017

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“…Our findings add another Rab GTPase to the list of possible therapeutic strategies for PD. Rab1 rescued neuron loss resulting from a-synuclein over-expression in flies (Cooper et al 2006) and partially corrected motor deficits in a rat model of PD (Coune et al 2011). Rab8 protected from a-synuclein-induced toxicity in flies (Yin et al 2014).…”

Section: Rab7 Protects From A-synuclein Toxicitymentioning

confidence: 95%

Rab7 induces clearance of α‐synuclein aggregates

Dinter

Saridaki

Nippold

et al. 2016

Journal of Neurochemistry

105

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Parkinson's disease can be caused by mutations in the α-synuclein gene and is characterized by aggregates of α-synuclein protein. Aggregates are degraded by the autophago-lysosomal pathway. Since Rab7 has been shown to regulate trafficking of late endosomes and autophagosomes, we hypothesized that over-expressing Rab7 might be beneficial in Parkinson's disease. To test this hypothesis, we expressed the pathogenic A53T mutant of α-synuclein in HEK293 cells and Drosophila melanogaster. In HEK293 cells, EGFP-Rab7-decorated vesicles contain α-synuclein. Rab7 over-expression reduced the percentage of cells with α-synuclein particles and the amount of α-synuclein protein. Time-lapse microscopy confirmed that particles frequently disappeared with Rab7 over-expression. Clearance of α-synuclein is explained by the increased occurrence of acidified α-synuclein vesicles with Rab7 over-expression, presumably representing autolysosomes. Rab7 over-expression reduced apoptosis and the percentage of dead cells in trypan blue staining. In the fly model, Rab7 rescued the locomotor deficit induced by neuronal expression of A53T-α-synuclein. These beneficial effects were not produced by Rab7 missense mutations causing Charcot Marie Tooth neuropathy, or by the related GTPases Rab5, Rab9, or Rab23. Using mass spectrometry, we identified Rab7 in neuromelanin granules purified from human substantia nigra, indicating that Rab7 might be involved in the biogenesis of these possibly protective, autophagosome-like organelles in dopaminergic neurons. Taken together, Rab7 increased the clearance of α-synuclein aggregates, reduced cell death, and rescued the phenotype in a fly model of Parkinson's disease. These findings indicate that Rab7 is rate-limiting for aggregate clearance, and that Rab7 activation may offer a therapeutic strategy for Parkinson's disease. Cells over-expressing aggregation-prone A53T alpha-synuclein develop cytoplasmic aggregates mimicking changes observed in Parkinson's disease. When following cells in time-lapse microscopy, some few cells are able to remove these aggregates (Opazo et al. 2008). We now show that the percentage of cells clearing all aggregates from their cytosol is greatly increased with Rab7 over-expression, indicating that availability of Rab7 is rate-limiting for autophagic clearance of aggregates. The functional significance of this effect in neurons was confirmed in a Drosophila melanogaster model of Parkinson's disease.

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“…It was subsequently shown that α-synuclein overexpression impairs Rab1A activity and thus hinders the formation of autophagosome by interfering with Atg9 function 63 . Moreover, increased Rab1 production is sufficient to correct α-synuclein-mediated Golgi fragmentation, dopaminergic (DA) neuron loss, and motor deficits in mammalian animal models of PD 10, 11 . These observations suggest that Rab1A plays a crucial role in the pathogenesis of PD and is a potential therapeutic target for a disease currently lacking effective medicine.…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

Rab1 in cell signaling, cancer and other diseases

Yang

Zhang

et al. 2016

Oncogene

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The ER and Golgi membrane system plays major roles in cell signaling and regulation of the biosynthesis/transport of proteins and lipids in response to environmental cues such as amino acid and cholesterol levels. Rab1 is the founding member of the Rab small GTPase family, which is known to mediate dynamic membrane trafficking between ER and Golgi. Growing evidence indicate that Rab1 proteins have important functions beyond their classical vesicular transport functions, including nutrient sensing and signaling, cell migration, and presentation of cell surface receptors. Moreover, deregulation of RAB1 expression has been linked to a myriad of human diseases such as cancer, cardiomyopathy and Parkinson’s disease. Further investigating these new physiological and pathological functions of Rab1 should provide new opportunities for better understanding of the disease processes and may lead to more effective therapeutic interventions.

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Rab1A Over-Expression Prevents Golgi Apparatus Fragmentation and Partially Corrects Motor Deficits in an Alpha-Synuclein Based Rat Model of Parkinson's Disease

Cited by 60 publications

References 41 publications

Tau secretion is correlated to an increase of Golgi dynamics

Tau secretion is correlated to an increase of Golgi dynamics

Rab7 induces clearance of α‐synuclein aggregates

Rab1 in cell signaling, cancer and other diseases

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