Four inherited neurodegenerative diseases—Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidolusian atrophy (DRPLA)—are linked to abnormally expanded glutamine repeats in the affected proteins. These repeats, located near the N-termini of the proteins, are thought to function as "polar zippers," potentially joining proteins together through hydrogen bonds, similar to leucine zippers in transcription factors. The length of these repeats correlates with disease severity and progression, with longer repeats leading to more severe symptoms and earlier onset. The expansion of these repeats is also observed in successive generations, particularly in males. The structure of poly(L-glutamine) was studied using molecular modeling and diffraction techniques, revealing that it forms β-sheets held together by hydrogen bonds. This structure suggests that glutamine repeats may act as polar zippers, facilitating interactions between proteins. The study also showed that the glutamine-rich segment of the HD protein forms a rigid helix, and its extension may lead to protein aggregation and precipitation in neurons, contributing to disease pathology. In SBMA, the androgen receptor contains an expanded glutamine-rich segment, which may lead to abnormal transcriptional activity. In SCA1, the glutamine repeat length varies significantly between healthy individuals and those with the disease. The study also examined the function of glutamine repeats in transcription factors, such as Sp1, where the glutamine-rich segment was shown to enhance transcription when bound to DNA. The molecular pathology of these diseases suggests that the expansion of glutamine repeats leads to gain of function rather than loss of function. The abnormal aggregation of proteins due to extended glutamine repeats may cause neural degeneration, explaining the symptoms observed in these diseases. The study provides evidence that glutamine repeats may function as polar zippers, contributing to the pathogenesis of these neurodegenerative diseases.Four inherited neurodegenerative diseases—Huntington disease (HD), spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidolusian atrophy (DRPLA)—are linked to abnormally expanded glutamine repeats in the affected proteins. These repeats, located near the N-termini of the proteins, are thought to function as "polar zippers," potentially joining proteins together through hydrogen bonds, similar to leucine zippers in transcription factors. The length of these repeats correlates with disease severity and progression, with longer repeats leading to more severe symptoms and earlier onset. The expansion of these repeats is also observed in successive generations, particularly in males. The structure of poly(L-glutamine) was studied using molecular modeling and diffraction techniques, revealing that it forms β-sheets held together by hydrogen bonds. This structure suggests that glutamine repeats may act as polar zippers, facilitating interactions between proteins. The study also showed that the glutamine-rich segment of the HD protein forms a rigid helix, and its extension may lead to protein aggregation and precipitation in neurons, contributing to disease pathology. In SBMA, the androgen receptor contains an expanded glutamine-rich segment, which may lead to abnormal transcriptional activity. In SCA1, the glutamine repeat length varies significantly between healthy individuals and those with the disease. The study also examined the function of glutamine repeats in transcription factors, such as Sp1, where the glutamine-rich segment was shown to enhance transcription when bound to DNA. The molecular pathology of these diseases suggests that the expansion of glutamine repeats leads to gain of function rather than loss of function. The abnormal aggregation of proteins due to extended glutamine repeats may cause neural degeneration, explaining the symptoms observed in these diseases. The study provides evidence that glutamine repeats may function as polar zippers, contributing to the pathogenesis of these neurodegenerative diseases.