Huntington Disease as a Neurodevelopmental Disorder and Early Signs of the Disease in Stem Cells

Abstract

Huntington disease (HD) is a dominantly inherited disorder caused by a CAG expansion mutation in the huntingtin (HTT) gene, which results in the HTT protein that contains an expanded polyglutamine tract. The adult form of HD exhibits a late onset of the fully symptomatic phase. However, there is also a long presymptomatic phase, which has been increasingly investigated and recognized as important for the disease development. Moreover, the juvenile form of HD, evoked by a higher number of CAG repeats, resembles a neurodevelopmental disorder and has recently been the focus of additional interest. Multiple lines of data, such as the developmental necessity of HTT, its role in the cell cycle and neurogenesis, and findings from pluripotent stem cells, suggest the existence of a neurodevelopmental component in HD pathogenesis. Therefore, we discuss the early molecular pathogenesis of HD in pluripotent and neural stem cells, with respect to the neurodevelopmental aspects of HD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0477-7) contains supplementary material, which is available to authorized users.

Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes

“…Thus, different parts of the protein are involved in different functions during early development and late in life. Abnormal brain development has also been linked to the loss of HTT (6) and increasing evidence suggests a neurodevelopmental component in HD (7,8). However, what remains poorly understood is whether the increased striatal and cortical neuronal vulnerability caused by muHTT is due to specific effects in the adult brain or if it is caused by abnormal development that leads to neurodegeneration in late life.…”

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

“…3). Cells in this early developmental stage display increased activity of DNA repair systems, 30 and the higher expression levels at larger CAG lengths could be the result of preventative mechanisms relating to the repeat expansion. Conversely, protein levels for these genes were decreased in HD patient brains compared to controls (Fig.…”

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

“…Increased cell proliferation in HD patient brains proportional to disease grade in the subependymal layer that overlies the degenerating caudate nucleus (Curtis et al, 2003(Curtis et al, , 2005 suggests increased neurogenesis in the adult brain, potentially as an adaptation to disease. Using HD iPSCderived neuronal cultures and differentiated embryonic stem cells (ESCs), dysregulation of neurodevelopmental pathways implicates deficits in striatal maturation (Wiatr et al, 2018). These signaling deficits occur early and are associated with phenotypes such as increased vulnerability to growth factor withdrawal in persistent neural progenitors (Mattis et al, 2014;Ring et al, 2015), suggesting that while neurogenesis is initiated, neuronal maturation may be impaired, leaving developmentally arrested cells vulnerable to cellular stressors.…”