No abstract

Huntington’s disease (HD) is an autosomal-dominant inherited progressive neurodegenerative disorder. It is caused by a CAG repeat expansion in the Huntingtin gene that is translated to an expanded polyglutamine (PolyQ) repeat in huntingtin protein. HD is characterized by mood swings, involuntary movement, and cognitive decline in the late disease stage. HD patients often die 15–20 years after disease onset. Currently, there is no cure for HD. Due to the striking neuronal loss in HD, most studies focused on the investigation of the predominantly neuronal degeneration in specific brain regions. However, the pathology of the white matter area in the brains of HD patients was also reported by clinical imaging studies, which showed white matter abnormalities even before the clinical onset of HD. Since oligodendrocytes form myelin sheaths around the axons in the brain, white matter lesions are likely attributed to alterations in myelin and oligodendrocyte-associated changes in HD. In this review, we summarized the evidence for white matter, myelin, and oligodendrocytes alterations that were previously observed in HD patients and animal models. We also discussed potential mechanisms for white matter changes and possible treatment to prevent glial dysfunction in HD.

Huntington disease (HD) is caused by the expansion of CAG triplet repeats in exon 1 of the huntingtin (HTT) gene, which also encodes the first 17 amino acids (N-17) that can modulate the toxicity of the expanded polyQ repeat. N-17 are conserved in a wide range of species and are found to influence the subcellular distribution of mutant Htt. Moreover, N-17 is subject to many posttranslational modifications that may regulate the function, stability, and distribution of HTT. However, the function of Htt exon 1 and its influence on the normal Htt remains to be fully investigated. By investigating a knock-in mouse model that lacks Htt exon1, we found that deletion of Htt exon1 does not affect the survival of mice and differentiation of cultured mouse neurons. Furthermore, the lack of Htt exon 1 does not alter the subcellular distribution of Htt, autophagy protein expression, and global gene transcription in the mouse brain. These results suggest that removing the entire exon 1 of Htt could be a therapeutic approach to eliminate expanded polyQ toxicity.

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.

Under weightlessness condition, the vasoconstriction will present the regional specific change. This study is to explore the role of myofilament Ca2+ sensitivity and its regulator RhoA-ROCK in these alterations, and the effect of tetramethylpyrazine on it. Female SD Rats tail suspending was used to simulate weightlessness. This study found that in weightless carotid artery, the vasoconstriction induced by PHE and KCl enhanced. The Ca2+ sensitivity, the protein expression of RhoA and ROCK II, and the phosphorylation level of MYPT1 and MLC increased. Tetramethylpyrazine administration for weightless rats could weaken the vasoconstriction, decrease the Ca2+ sensitivity, and reduce the above protein expressions and phosphorylation levels. Pretreatment with Y-27632 to inhibit the ROCK activity could decrease the vasoconstriction and the Ca2+ sensitivity in weightless rats, but have no effect in weightlessness plus tetramethylpyrazine administration rats. In weightless mesenteric artery, the vasoconstriction weakened. The Ca2+ sensitivity, the above protein expressions and phosphorylation levels decreased. Both tetramethylpyrazine administration and pretreatment with Y-27632 had no effects in weightlessness rats. These results suggest that the distinct alteration of myofilament Ca2+ sensitivity regulated by RhoA-ROCK possibly is the key factor resulting in the weightless vasoconstriction presenting different changes. Tetramethylpyrazine can inhibit the RhoA-ROCK protein expression to depress the enhanced weightless vasoconstriction in anterior part of body, but has no influence on the weakened vasoconstriction in posterior part of body. The present study clarifies the change of Ca2+ sensitivity and its mechanism in weightless artery, and broadens the application of tetramethylpyrazine in the treatment of vascular weightless dysfunction.