polyglutamine

Polyglutamine, or polyQ, refers to a tract of consecutive glutamine residues within a protein. In human genes, polyQ tracts are encoded by CAG trinucleotide repeats. When the number of repeats remains within the normal range, the protein functions largely normally; when repeats expand beyond a disease-associated threshold, the protein tends to misfold and form intracellular aggregates, particularly in neurons, contributing to neurodegenerative disease. Some repeats include CAA interruptions, which can influence stability and disease risk.

Genetic basis and diseases: PolyQ expansion diseases include Huntington disease (HTT gene) and several spinocerebellar ataxias (SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA17), dentatorubral-pallidoluysian atrophy (DRPLA), and Kennedy disease (spinal and bulbar muscular atrophy, SBMA). The pathogenic threshold and clinical course vary by gene but expansions above roughly 35–40 glutamines are commonly associated with disease. Longer repeats typically correlate with earlier onset, a phenomenon known as anticipation.

Pathophysiology: The diseases are generally caused by a toxic gain of function from the polyQ-containing protein, leading to misfolding and aggregation that disrupt cellular processes. Nuclear inclusions and impaired proteostasis, transcriptional dysregulation, and mitochondrial dysfunction are frequently reported. The exact clinical manifestations depend on which gene is affected and which neural circuits are impacted.

Diagnosis and treatment: Diagnosis relies on genetic testing to determine CAG repeat length in the relevant gene. There is no cure; management is supportive and multidisciplinary. Research areas include approaches to silence the mutant transcript or reduce the toxic protein, and to enhance cellular clearance of aggregates.