Editors' ChoiceNeurodegenerative Disease

Is Huntington’s disease a neurodevelopmental disorder?

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Science Translational Medicine  06 Jan 2016:
Vol. 8, Issue 320, pp. 320ec1
DOI: 10.1126/scitranslmed.aad9760

Huntington’s disease (HD) is an inherited neurodegenerative disease that manifests in adulthood, typically between 30 and 50 years of age. Although genetic tests can now predict accurately whether an individual will be affected, currently there is neither a cure for HD nor a treatment to delay its onset and progression. By the time patients present with symptoms, the death of striatal neurons in the brain is well under way, and the damage may not be reversible.

An alternative strategy is to understand the molecular changes that precede neuronal death. If researchers can identify when the first indications of abnormal striatal neuronal function occur, this might permit therapeutic interventions prior to cell loss and the onset of disease symptoms. This is the approach taken by Ring et al. in their new study. These investigators reprogrammed fibroblasts from patients with Huntington’s disease into induced pluripotent stem cells, which were subsequently differentiated into neural stem cells (NSCs) with gene expression patterns thought to resemble those found in the developing human brain. Surprisingly, genome-wide expression profiling of the HD NSCs, when compared with corrected isogenic control NSCs, identified perturbed expression of genes in the TFG-β, netrin-1, and Sema3D pathways. Not only were these findings replicated in mouse models of HD, but also manipulation of these gene pathways ameliorated deficits in HD NSCs such as impaired mitochondrial function.

Surprisingly, this study, which implicates dysregulation of genes involved in neuronal development and formation of the dorsal striatum, suggests that the first disease processes in HD manifest during early embryonic development, prior to full neuronal maturation. If true, this greatly expands both the time window for clinical intervention as well as the range of putative therapeutic targets that might prevent, delay or cure HD in affected individuals before the onset of disease symptoms in adulthood.

K. L. Ring et al., Genomic analysis reveals disruption of striatal neuronal development and therapeutic targets in human Huntington’s disease neural stem cells. Stem Cell Rep. 5, 1023–1038 (2015). [Full Text]

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