The article explores the role of abnormally expanded glutamine repeats in four inherited neurodegenerative diseases: Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidolysian atrophy (DRPLA). These repeats are found near the N-termini of the affected proteins and tend to lengthen in successive generations, particularly in male transmissions. The authors propose that these glutamine repeats function as polar zippers, joining protein molecules together, similar to how leucine zippers join transcription factors. Molecular modeling and experimental studies, including optical, electron, and X-ray diffraction, show that poly(L-glutamine) forms β-sheets held together by hydrogen bonds. The extension of these repeats may cause disease by increasing nonspecific affinity between factors or by gradually precipitating the affected proteins in neurons. The article also discusses the possible functions of glutamine repeats in normal transcriptional regulation and the molecular pathology of these diseases, suggesting that the gain of function in these diseases may lead to aberrant transregulatory activity or protein aggregation.The article explores the role of abnormally expanded glutamine repeats in four inherited neurodegenerative diseases: Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidolysian atrophy (DRPLA). These repeats are found near the N-termini of the affected proteins and tend to lengthen in successive generations, particularly in male transmissions. The authors propose that these glutamine repeats function as polar zippers, joining protein molecules together, similar to how leucine zippers join transcription factors. Molecular modeling and experimental studies, including optical, electron, and X-ray diffraction, show that poly(L-glutamine) forms β-sheets held together by hydrogen bonds. The extension of these repeats may cause disease by increasing nonspecific affinity between factors or by gradually precipitating the affected proteins in neurons. The article also discusses the possible functions of glutamine repeats in normal transcriptional regulation and the molecular pathology of these diseases, suggesting that the gain of function in these diseases may lead to aberrant transregulatory activity or protein aggregation.