TY - JOUR

T1 - Regulation of HTT mRNA Biogenesis: The Norm and Pathology

AU - Zubkova, Alexandra E.

AU - Yudkin, Dmitry V.

N1 - This research work was supported by the Academic leadership program Priority 2030 proposed by Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University). Zubkova, A. E. Regulation of HTT mRNA Biogenesis: The Norm and Pathology / A. E. Zubkova, D. V. Yudkin // International Journal of Molecular Sciences. – 2024. – Vol. 25, No. 21. – P. 11493. – DOI 10.3390/ijms252111493.

PY - 2024/10/26

Y1 - 2024/10/26

N2 - Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators.

AB - Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators.

KW - CAG repeat

KW - Huntington’s disease

KW - alternative splicing

KW - incomplete splicing

KW - mRNA processing

KW - miRNA

KW - transcriptional regulatory elements

KW - Humans

KW - Gene Expression Regulation

KW - Huntingtin Protein/genetics

KW - RNA, Messenger/genetics

KW - Animals

KW - Huntington Disease/genetics

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85208570918&origin=inward&txGid=655e84f4c610a1584bd60df95bb6b20b

UR - https://www.mendeley.com/catalogue/0114a8fd-7cb9-393f-99a1-068424336829/

UR - https://www.elibrary.ru/item.asp?id=74983590

UR - https://pubmed.ncbi.nlm.nih.gov/39519046/

UR - https://pmc.ncbi.nlm.nih.gov/articles/PMC11546943/

U2 - 10.3390/ijms252111493

DO - 10.3390/ijms252111493

M3 - Review article

C2 - 39519046

VL - 25

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 21

M1 - 11493

ER -