Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities (original) (raw)

2020, Nature Reviews Neurology

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the HTT gene and involves a complex web of pathogenic mechanisms. Mutant HTT disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are amongst the earliest detectable changes in individuals with premanifest HD, and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of a HTT-lowering antisense oligonucleotide successfully, and safely, reduced CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself. direction-dependence might be because CAG and CTG repeats have different propensities to form slipped structures, or are processed differently by repair machinery. Excitingly, most of the HD-modifying variants and pathways converge on specific DNA repair mechanisms, particularly mismatch repair, and influence somatic instability 98,110,112,117,122. These observations suggest that downregulation of MSH3, MutLα, MutLγ and LIG1, the inhibition of interactions between them, or the upregulation of FAN1 and PMS1, could reduce somatic CAG expansion and improve the course of HD (Acknowledgements S.J.T.