Kuperman, Y. | Search bioRxiv

bioRxiv2023

Lowering mutant huntingtin by small molecules relieves Huntington's disease symptoms and progression

Huntingtons disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutant Htt expression is considered the leading therapeutic approach for HD. We report the identification of novel small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression and improved motor and anxious-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier and prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD.

molecular biology↗

bioRxiv2022

Store-operated Ca2+ entry regulatory factor (SARAF) alters murine metabolic state in an age-dependent manner via hypothalamic pathways.

Store-operated Ca2+ entry (SOCE) is a vital process aimed at refilling cellular internal Ca2+ stores, and a primary cellular-signaling driver of transcription factors entry to the nucleus. SARAF (SOCE associated regulatory factor)/TMEM66 is an endoplasmic reticulum (ER) resident transmembrane protein that promotes SOCE inactivation and prevents Ca2+ overfilling of the cell. Here we demonstrate that mice deficient in SARAF develop age-dependent sarcopenic obesity with decreased energy expenditure, lean mass and locomotion without affecting food consumption. Moreover, SARAF ablation reduces hippocampal proliferation, modulates the activity of the hypothalamus-pituitary-adrenal (HPA) axis, and mediates changes in anxiety-related behaviors. Interestingly, selective SARAF ablation in the paraventricular nucleus (PVN) of the hypothalamus protects from old age-induced obesity and preserves locomotion, lean mass and energy expenditure, suggesting an opposing, site-specific role for SARAF. Lastly, SARAF ablation in hepatocytes leads to elevated SOCE, elevated vasopressin-induced Ca2+ oscillations, and an increased mitochondrial spare respiratory capacity, thus providing insights into the cellular mechanisms that may affect the global phenotypes. These effects may be mediated via the liver X receptor (LXR) and IL-1 signaling metabolic regulators explicitly altered in SARAF ablated cells. In short, our work supports both central and peripheral roles of SARAF in regulating metabolic, behavioral, and cellular responses. HighlightsO_LILoss/absence of SARAF facilitates age-dependent obesity with decreased metabolic rate, lean mass, and locomotion, without affecting food consumption. C_LIO_LILoss of SARAF leads to lipid droplet hypertrophy, BAT whitening and age-dependent hepatic steatosis. C_LIO_LIMice lacking SARAF expression in the PVN have an increased metabolic rate, decreased BAT whitening, and are protected from sarcopenic obesity. C_LIO_LISARAF ablation in hepatocytes increases SOCE, elevates Ca2+ oscillation in response to vasopressin, and increases the mitochondrias spare respiratory capacity. C_LIO_LILoss of SARAF leads to decreased hippocampal proliferation, sensitized HPA-axis and changes in anxiety-related behavior. C_LI

physiology↗