Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and Activates Autophagy

Mealer, Robert G.; Murray, Alexandra; Shahani, Neelam; Subramaniam, Srinivasa; Snyder, Solomon H.

doi:10.1074/jbc.m113.536912

Cited by 116 publications

(126 citation statements)

References 43 publications

(58 reference statements)

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“…RHES was initially thought to augment striatal HTT neurotoxicity, in part by activating mTOR 114 . However, subsequent studies demonstrated that RHES deletion decreased autophagy, whereas RHESs overexpression activated autophagy independent of mTOR 115 . Activation of autophagy protects against mutant HTT accumulation and toxicity, enhances HTT clearance, and slows disease progression by mTOR-dependent and mTOR-independent mechanisms.…”

Section: Huntington Diseasementioning

confidence: 94%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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Section: Huntington Diseasementioning

confidence: 94%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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“…Yet, poly-Qexpanded Htt may also exert a tissue-specific increase in mTORC1 signaling, for example, by interacting with tissue-specific regulators of mTOR. Previously, we showed that poly-Q Htt interacts with the striatal-enriched SUMO-E3-GTPase Rhes, which SUMOylates poly-Q-expanded Htt and increases its toxicity (10,17,(69)(70)(71). Because Rhes also activates mTORC1 (11), we hypothesize that the interaction of poly-Q-expanded Htt with Rhes may lead to abnormally high activation of mTORC1 in the striatum that may cause early and prominent striatal dysfunction in HD (72).…”

Section: Depletion Of Tsc1 In An Hd Mouse Model Increases Behavioral mentioning

confidence: 95%

Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

et al. 2014

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In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons in the striatum, which impairs motor and cognitive functions. Identifying the physiological role and molecular functions of Htt may yield insight into HD pathogenesis. We found that Htt promotes signaling by mTORC1 [mechanistic target of rapamycin (mTOR) complex 1] and that this signaling is potentiated by poly-Q-expanded Htt. Knocking out Htt in mouse embryonic stem cells or human embryonic kidney cells attenuated amino acid-induced mTORC1 activity, whereas overexpressing wild-type or poly-Q-expanded Htt in striatal neuronal cells increased basal mTOR activity. Striatal cells expressing endogenous poly-Q-expanded Htt showed an increase in the number and size of mTOR puncta on the perinuclear regions compared to cells expressing wild-type Htt. Pull-down experiments indicated that amino acids stimulated the interaction of Htt and the guanosine triphosphatase (GTPase) Rheb (a protein that stimulates mTOR activity), and that Htt forms a ternary complex with Rheb and mTOR. Pharmacologically inhibiting PI3K (phosphatidylinositol 3-kinase) or knocking down Rheb abrogated mTORC1 activity induced by expression of a poly-Q-expanded amino-terminal Htt fragment. Moreover, striatum-specific deletion of TSC1, encoding tuberous sclerosis 1, a negative regulator of mTORC1, accelerated the onset of motor coordination abnormalities and caused premature death in an HD mouse model. Together, our findings demonstrate that mutant Htt contributes to the pathogenesis of HD by enhancing mTORC1 activity.

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“…High expression of the Rhes protein in the striatum supports increased mHtt lifetime in this region: Rhes binds to mHtt and promotes its sumoylation, which increases the levels of soluble mHtt and reduces mHtt ubiquitination and aggregation (Subramaniam et al, 2009). Moreover, studies in PC12 cells indicate that Rhes binds Beclin-1 and activates autophagy, and that this Rhes-induced autophagic activation is blocked by mHtt co-expression (Mealer et al, 2014). The mechanisms behind differential mHtt proteostasis in striatal and cortical neurons may thus involve differences in autophagy, being relevant that striatal neurons with higher autophagic flux (lower LC3 mean lifetime) were found to survive longer in the presence of mHtt (Tsvetkov et al, 2013).…”

Section: Mitophagy and Huntingtin Proteostasismentioning

confidence: 99%

Mitochondrial dynamics and quality control in Huntington's disease

Guedes-Dias

Pinho

Soares

et al. 2016

Neurobiology of Disease

104

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Huntington's disease (HD) is an inherited neurodegenerative disorder caused by polyglutamine expansion mutations in the huntingtin protein. Despite its ubiquitous distribution, expression of mutant huntingtin (mHtt) is particularly detrimental to medium spiny neurons within the striatum. Mitochondrial dysfunction has been associated with HD pathogenesis. Here we review the current evidence for mHtt-induced abnormalities in mitochondrial dynamics and quality control, with a particular focus on brain and neuronal data pertaining to striatal vulnerability. We address mHtt effects on mitochondrial biogenesis, protein import, complex assembly, fission and fusion, mitochondrial transport, and on the degradation of damaged mitochondria via autophagy (mitophagy). For an integrated perspective on potentially converging pathogenic mechanisms, we also address impaired autophagosomal transport and abnormal mHtt proteostasis in HD.

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Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and Activates Autophagy

Cited by 116 publications

References 43 publications

The mTOR signalling cascade: paving new roads to cure neurological disease

The mTOR signalling cascade: paving new roads to cure neurological disease

Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

Mitochondrial dynamics and quality control in Huntington's disease

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