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Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length‐dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP‐43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP‐43 is mislocalized in the cytoplasm. By investigating HD knock‐in mice, we explore whether the pathogenic TDP‐43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP‐43 without nuclear localization signal. We found that the cytoplasmic TDP‐43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP‐43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre‐mRNA, promotes the transport of exon1‐intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP‐43 contributes to HD pathogenesis via its binding to and transport of nuclear un‐spliced mRNA to the ribosome for the generation of a toxic protein product. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that non‐neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP‐43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP‐43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate‐specific cleavage of truncated TDP‐43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP‐43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP‐35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP‐35 in cytoplasm, the downstream myelin‐associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP‐43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP‐43 related diseases. [ABSTRACT FROM AUTHOR]