Reinstating Aberrant mTORC1 Activity in Huntington’s Disease Mice Improves Disease Phenotypes

Abstract

Summary Huntington's Disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is early and robust vulnerability in striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in HD brain and show that introducing the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, impaired dopamine signaling, and increases autophagy. We also find that the expression of Rhes, a striatum-enriched mTOR activator, is reduced in HD patient and mouse brain, and that exogenous addition of Rhes alleviates motor deficits and improves brain pathology in HD mice. Our combined work indicates that impaired Rhes/mTORC1 activity in HD brain may underlie the notable striatal susceptibility and thus presents a promising therapeutic target for HD therapy.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…Similarly, deficits in the levels of the mTORC1 regulator RHEB in YAC128 HD mice were reversed by pridopidine treatment. Increasing RHEB activity was recently shown to ameliorate a number of cellular and molecular deficits in HD mice, including mitochondrial deficits and cholesterol dyshomeostasis (58). Finally, pridopidine treatment rescued deficits in DUSP1, a member of the mitogen-activated protein kinase family of phosphatases recently shown to be protective in animal models of HD (59).…”

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

“…Besides its well-established expression within striatal GABAergic medium spiny-projecting neurons, we recently demonstrated that Rasd2 is also virtually localized in all cholinergic interneurons in humans and mice, where it affects DA D2R-dependent firing activity and signaling (Sciamanna et al, 2015). On the other hand, Rasd2 is able to modulate AKT and mTOR signaling cascades Subramaniam et al, 2012), well known to be involved in neurological (Lee et al, 2015) and psychiatric disorders (Emamian et al, 2004). Accordingly, the interaction between mTOR and mutant Huntingtin disrupts mTORC1 function and predisposes the striatum to the early degeneration in Huntington's disease (Lee et al, 2015).…”

“…On the other hand, Rasd2 is able to modulate AKT and mTOR signaling cascades Subramaniam et al, 2012), well known to be involved in neurological (Lee et al, 2015) and psychiatric disorders (Emamian et al, 2004). Accordingly, the interaction between mTOR and mutant Huntingtin disrupts mTORC1 function and predisposes the striatum to the early degeneration in Huntington's disease (Lee et al, 2015). On the other hand, alterations of AKT1-GSK3β signaling in schizophrenic patients have identified AKT1 as one of the potential susceptibility genes involved in such a psychiatric disorder (Emamian et al, 2004).…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…However, recently, it was found that mTORC1 activity is reduced in striatum tissues of HD patients and consequently mTORC1 activation by introducing the constitutively active form of Rheb could alleviate metabolic and degenerative phenotypes in HD brain (Lee et al, 2015). This was surprising since mTORC1 inhibits autophagy and it is possible that autophagy is regulated by other pathways, for example by the proteasomal degeradation, independent of mTORC1 (Sarkar and Rubinsztein, 2008).…”

“…Protective effects may also result from the ability of mTORC1 to promote the lipogenic gene expression via sterol regulatory element-binding proteins (SREBPs) mediated transactivation (Zhang and Manning, 2015). There were also reports that Rhes, a striatum enriched protein, was able to improve neuropathological and motor phenotypes in HD mice (Lee et al, 2015). This effect of Rhes is mediated by promotion of autophagy independent of mTORC1 activation by binding to Beclin-1, a protein critical for the induction of autophagy (Mealer et al, 2014).…”