Mutant huntingtin exon 1 polyglutamine aggregates (mHTT exon 1 aggregates)

Mutant huntingtin exon 1 polyglutamine aggregates are the primary pathological hallmark of Huntington's disease (HD), a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene (Source: NIH, PubMed). These aggregates form when the huntingtin protein contains an abnormally long polyglutamine (polyQ) tract, which causes the protein to misfold and self-assemble into toxic oligomers and insoluble fibrils (Source: NIH, Frontiers in Molecular Neuroscience). The aggregation process, particularly involving the N-terminal exon 1 fragment, leads to the sequestration of vital cellular components, including transcription factors and molecular chaperones, thereby disrupting proteostasis and gene expression (Source: NIH, MDPI). Therapeutic interventions aim to prevent the formation of these aggregates, disrupt existing fibrils, or enhance their clearance through pathways like autophagy (Source: NIH, Frontiers in Molecular Neuroscience). Recent advancements include the development of specific PET tracers, such as [11C]CHDI-180, that bind to these aggregates to monitor disease progression and target engagement in clinical trials (Source: NIH, VJNeurology).

Other names

mHTT aggregatesmHTT fibrilsPolyglutamine aggregatesHuntingtin exon 1 inclusion bodiesN-terminal huntingtin fragmentsmHTT exon 1 polyQ aggregates

Drugs targeting these aggregates work by inhibiting the initial misfolding and nucleation of mutant huntingtin monomers, disrupting the elongation of existing fibrils, or enhancing the cellular clearance of aggregates through the activation of autophagy and the ubiquitin-proteasome system (Source: NIH, Frontiers in Molecular Neuroscience).