Mutant Huntingtin protein (mHTT) (mHTT)

Mutant Huntingtin protein (mHTT) is the pathogenic form of the huntingtin protein, resulting from an expanded cytosine-adenine-guanine (CAG) repeat in exon 1 of the HTT gene [1, 3]. This expansion leads to an abnormally long polyglutamine (polyQ) tract, which causes the protein to misfold and self-assemble into high molecular weight (HMW) aggregates, including soluble oligomers and insoluble amyloid-like fibrils [2, 4]. These aggregates are the primary neuropathological hallmark of Huntington's disease (HD), a progressive and fatal neurodegenerative disorder characterized by motor, cognitive, and psychiatric decline [5, 13]. The aggregates exert toxicity through a toxic gain of function, disrupting essential cellular processes such as axonal transport, mitochondrial function, and transcriptional regulation, while also sequestering vital chaperones and other proteins [3, 15]. Therapeutic strategies targeting these species include small molecules designed to inhibit aggregation or promote clearance via autophagy, as well as genetic approaches like antisense oligonucleotides (ASOs) and RNA interference (RNAi) that aim to lower overall mHTT levels [5, 14]. Monitoring these species in patients is increasingly facilitated by biomarkers such as mHTT levels in cerebrospinal fluid and novel PET imaging tracers [8, 9, 10].

Other names

mHTT aggregatesmHTTex1 fibrilsPolyglutamine aggregatesInclusion bodiesHigh molecular weight mHTT speciesN-terminal huntingtin fragments

Inhibition of protein aggregation, promotion of autophagic clearance, and reduction of mutant protein synthesis via antisense oligonucleotides, RNA interference, or splicing modulation [3, 5, 15].