Huntington’s disease (HD) is caused by CAG / polyglutamine repeat expansions in the huntingtin (htt) gene, yielding proteins that misfold and resist degradation. HD belongs to a large class of neurodegenerative proteinopathies including Alzheimer’s disease, Parkinson’s disease, and tauopathies. Previous studies demonstrated that mutant htt interferes with transcriptional programs coordinated by PPARγ co-activator 1α (PGC-1α), a regulator of mitochondrial biogenesis and oxidative stress. To test if restoration of PGC-1α could treat HD, we attempted an in vivo genetic rescue in mice. We found that PGC-1α induction ameliorates HD neurodegeneration and virtually eliminates htt protein aggregation, in part by attenuating oxidative stress. Further studies revealed that PGC-1α promotes htt turnover and aggregate elimination by transactivation of TFEB, a master regulator of the autophagy-lysosome pathway, and that TFEB alone is capable of reducing htt aggregation and neurotoxicity, placing PGC-1α upstream of TFEB. PGC-1α and TFEB thus hold great promise as therapies for HD and other neurodegenerative proteinopathies.

sue lysate was incubated overnight at 4°C with 50 μl of the mRNA cap analogue m 7

SUMMARY Macroautophagy (hereafter autophagy) is the major pathway by which macromolecules and organelles are degraded. Autophagy is regulated by the mTOR signaling pathway – the focal point for integration of metabolic information, with mTORC1 playing a central role in balancing biosynthesis and catabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. Based upon transcriptome analysis of neurons subjected to nutrient deprivation, we identified let-7 microRNA as capable of promoting neuronal autophagy. We found that let-7 activates autophagy by coordinately down-regulating the amino acid sensing pathway to prevent mTORC1 activation. Let-7 induced autophagy in the brain to eliminate protein aggregates, establishing its physiological relevance for in vivo autophagy modulation. Moreover, peripheral delivery of let-7 anti-miR repressed autophagy in muscle and white fat, suggesting that let-7 autophagy regulation extends beyond CNS. Hence, let-7 plays a central role in nutrient homeostasis and proteostasis regulation in higher organisms.

Summary Obesity is a major risk factor driving the global type II diabetes pandemic. Yet, the molecular factors linking obesity to disease remain to be elucidated. Gender differences are apparent in humans and also observed in murine models. Here we link these differences to expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which upon HFD becomes significantly reduced in skeletal muscle and adipose tissue of male, but not female mice. Strikingly, restoring 4E-BP1 expression in male mice protects them against HFD-induced obesity and insulin resistance. Male 4E-BP1 transgenic mice also exhibit reduced white adipose tissue accumulation, accompanied by decreased circulating levels of leptin and triglycerides. Importantly, transgenic 4E-BP1 male mice are also protected from aging-induced obesity and metabolic decline on a normal diet. These results demonstrate that 4E-BP1 is a gender-specific suppressor of obesity that regulates insulin sensitivity and energy metabolism.