Polyglutaminecontaining

Polyglutamine-containing proteins, or polyQ proteins, are those that include long tracts of the amino acid glutamine. These polyglutamine tracts are encoded by CAG trinucleotide repeats in the corresponding genes. In most people the repeat length is within a normal range and the protein functions normally; when the CAG repeat expands beyond a disease-causing threshold, the resulting polyglutamine-containing protein tends to misfold and form aggregates.

PolyQ expansions are the genetic basis of a family of neurodegenerative disorders known as polyglutamine diseases. These include Huntington disease (caused by expansions in the HTT gene) and several spinocerebellar ataxias (such as SCA1, SCA2, SCA3/MJD, SCA6, SCA7, among others), as well as dentatorubral-pallidoluysian atrophy (DRPLA). Most cases are inherited in an autosomal dominant manner, and the age of onset often correlates inversely with the length of the polyQ tract, a phenomenon known as anticipation due to repeat instability.

Molecularly, expanded polyQ tracts promote protein misfolding and aggregation, leading to dysfunctional proteostasis, transcriptional dysregulation, and cellular stress. Aggregates can form nuclear inclusions and disrupt neuronal function, with selective vulnerability in certain brain regions contributing to the typical clinical features. Some polyQ proteins have normal regulatory roles in development and transcription, and normal-length repeats are compatible with health.

Research and therapy focus on reducing the toxic polyQ burden or enhancing cellular quality control. Approaches include antisense oligonucleotides to lower transcript levels, small molecules to inhibit aggregation, and strategies to boost autophagy and chaperone activity. While no cure exists, these efforts aim to slow progression and improve quality of life for affected individuals.