Huntington's disease (HD) is caused by an expansion of a CAG repeat in the gene that encodes the huntingtin protein (HTT). The exact function of HTT is still not fully understood, and previous studies have mainly focused on identifying proteins that interact with HTT to gain insights into its function. Numerous HTT-interacting proteins have been discovered, shedding light on the functions and structure of HTT. Most of these proteins interact with the N-terminal region of HTT. Among the various HTT-interacting proteins, huntingtin-associated protein 1 (HAP1) and HTT-interacting protein 1 (HIP1) have been extensively studied. Recent research has uncovered differences in the distribution of HAP1 in monkey and human brains compared to mice. This finding suggests that there may be species-specific variations in the regulation and function of HTT-interacting proteins. Understanding these differences could provide crucial insights into the development of HD. In this review, we will focus on the recent advancements in the study of HTT-interacting proteins, with particular attention to the differential distributions of HTT and HAP1 in larger animal models.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Huntington disease (HD) is an autosomal dominantly inherited fatal neurodegenerative disease. It affects motor, cognitive and psychiatric functions, and ultimately leads to death. The pathology of the disease is due to an expansion of CAG repeats in exon 1 of the huntingtin gene on chromosome 4, which produces a mutant huntingtin protein (mhtt). HD patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. A variety of symptomatic treatments (which target excitotoxicity, the dopamine pathway, caspases, aggregation, mitochondrial dysfunction, transcriptional dysregulation, mHtt, nucleic acid, neurodegeneration, fetal neural transplants, etc.) are currently available, and new symptomatic and potentially disease-modifying therapies are being actively developed. Recent advances in novel therapeutic strategies, including targeting mutant huntingtin (mhtt) and the htt gene, promise another wave of disease-modifying trials in the near future. A better appreciation of heterogeneous clinical phenomenology and immediate tractable treatment goals coupled with advances in new therapeutics heralds a golden age of HD treatment that will positively impact the quality of life and longevity of HD patients and inform advances in other inherited and neurodegenerative neurological disorders. In the present review literature, our aims to address the latest research on promising therapeutics based on influencing the hypothesized pathological mechanisms associated with HD.

The study of the impact of polyQ expansion driven proteotoxicity on cell metabolism has evi-denced NAD molecule as a central player in regulating metabolic response and cell repair in neurodegeneration. The decline in NAD intracellular levels represents a hallmark of ageing aris-ing from a dysregulation between NAD-consuming and biosynthetic enzymatic reactions in which NMNAT plays a key role. By an integrated bioanalytical and proteomic experimental design, the derangement of NAD metabolism deriving from the accumulation of polyQ-Htt protein has been analysed in Saccha-romices cerevisiae harbouring a 103Q-Htt and compared with wild-type Htt, in absence and in presence of a phenolic extract from EVOO, as a source of antioxidant bioactive compounds. Quantification of NAD and its precursors and proteomic analysis of the differential protein ex-pression has been performed by LC-DAD-MS. Chronological lifespan and NAD homeostasis was strongly impaired by proteotoxic polyQ-Htt, eliciting a depletion of NAD levels and accumulation of NaMN. In parallel a downregulation of Sirt2 expression levels has been observed. Phenolic extract administration had no meaningful ef-fects on NAD replenishment to prevent proteotoxicity. NaMN can represent a biomarker of accel-erated aging, and/or a signaling molecule for cell repair.