Challenges of the Polyglutamine Diseases: From Dysfunctional Neuronal Circuitries to Neuron-Specific CAG Repeat Instability

Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington's disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with CAG repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the cell-type-specific pathologies and their long pre-symptomatic latency have received less attention. However, recent advances in detecting the single-cell transcriptome alongside the length of tandem repeats in HD post-mortem brains have enabled the identification of the repeat size that triggers extensive transcriptional dysregulation and cell death in specific neurons. The first challenge is to understand better the complexity of movement coordination circuits, including the basal ganglia and cerebellum, and which of their neurons are most vulnerable to the CAG expansion in each disease. The second challenge is to detect the dynamic increase in CAG repeat length at single-cell resolution in vulnerable neurons. This will offer hope for identifying primary and secondary pathological events and developing targeted therapies for all tandem-repeat expansion diseases.