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

Abstract

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.

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

“…PERK and phospho-eIF2α levels are linked to BACE1 regulation and AD-related behavioral deficits (Devi and Ohno, 2010; Ma et al, 2013; O'Connor et al, 2008). We also found huntingtin serves as a new effector of Rheb GTPase to activate mTORC1 to modulate Huntington disease (HD)-related symptoms (Pryor et al, 2014). Though the role of P-eIF2α signaling in HD-symptoms is not clear, a recent study implicated p-eIF2α in HD cellular toxicity (Leitman et al, 2014).…”

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

“…mTOR inhibition by rapamycin administration attenuated HTT accumulation and aggregate formation, and protected against neurodegeneration in fly and mouse models of HD 99 . Overexpression of wild-type or polyglutamineexpanded HTT in striatal neurons increased basal mTOR activity, and striatum-specific deletion of Tsc1 accelerated the onset of motor co-ordination abnormalities and led to premature death in an HD mouse model 110 . Thus, mTOR activation could exacerbate neurodegeneration in HD, and mTOR inhibition might restore autophagy, thereby preventing cell death.…”

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…A failure in autophagy-dependent handling of misfolded proteins impedes the clearance of these substrates that are likely to accumulate within the cell. Therefore, a common pathogenesis underlying all these NDDs disorders has been linked to autophagy inhibition due to mTOR hyperactivation [52,54,94,95,96,97]. For instance, an increased mTOR activity correlates with accumulation of Aβ and hyperphosphorylated tau in AD brains [98,99].…”