Editors' ChoiceNeurodegeneration

Is mTOR a good guy or bad guy in Huntington’s disease?

Sci. Signal.  03 Feb 2015:
Vol. 8, Issue 362, pp. ec26
DOI: 10.1126/scisignal.aaa8163

Huntington’s disease (HD) is a neurodegenerative disorder caused by a genetic mutation in the protein huntingtin (HTT) that expands a polyglutamine tract and promotes its aggregation. How mutant HTT (mHTT) contributes to the disease is not clear. The kinase mTOR (mechanistic target of rapamycin) is implicated in HD pathology because it inhibits autophagy, a mechanism of intracellular particle degradation and recycling that is considered protective in HD. However, mTOR complex 1 (mTORC1) promotes many of the processes that mHTT impairs, and studies examining mTOR and its upstream regulators in cell-based and knockout mouse models are conflicting. Lee et al. attempted to clarify the role of mTOR by manipulating its upstream regulators in a striatal-specific manner in the N171-82Q mouse model of HD. The phosphorylation of ribosomal protein S6, a marker of mTORC1 activity, was decreased in the striatum of deceased human HD patients compared with controls, whereas the abundance of components of mTORC1 (mTOR and Raptor) were comparable. Inducing the striatal neuron-specific expression of a constitutively active mutant of the mTORC1 activator Rheb (Ras homolog enriched in the brain), caRheb, in N171-82Q mice increased the phosphorylation of S6 and increased the expression of genes encoding proteins that promote mitochondrial function, cholesterol synthesis, and autophagy (all of which are decreased in HD); decreased the expression of genes encoding proteins that promote mHTT aggregation; decreased the abundance of mHTT aggregates; decreased striatal atrophy; increased medium spiny neuron (MSN) size; and improved motor performance compared with controls. However, in the striatum, mTORC1 is predominantly regulated by Rhes (Ras homolog enriched in the striatum). The abundance of Rhes was decreased in HD patient and mouse striatum compared with controls, even prior to the onset of symptoms. Similar to caRheb expression, viral-mediated expression of wild-type Rhes in the striatum of the mHTT mice improved motor function, increased medium spiny neuron (MSN) size, and increased the expression of a gene encoding a mitochondrial transcriptional regulator. The expression of a mutant Rhes lacking its guanosine triphosphatase (GTPase) activity, which mediates activation of mTORC1, failed to improve motor performance. Thus, the findings suggest that the activation of mTORC1 may be beneficial in HD.

J. H. Lee, L. Tecedor, Y. Hong Chen, A. M. Monteys, M. J. Sowada, L. M. Thompson, B. L. Davidson, Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron 85, 303–315 (2015). [PubMed]