Huntington’s disease alters human neurodevelopment

Abstract

Although Huntington’s disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington’s disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carry the Huntington’s disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington’s disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington’s disease thus has a neurodevelopmental component and is not solely a degenerative disease.

Pluripotent stem cell derived models of neurological diseases reveal early transcriptional heterogeneity

“…In addition, inhibition of ECM1, which is associated with lipoid proteinosis that may result in epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage, resulted in a significant effect [52]. Interestingly, knockdown of HDAC3, which has a similar average expression and variability in HD NPCs, and was previously shown to be related to HD cognitive pathology and CAG repeat expansion but not to aggregate formation in mouse HD models [7], showed a slightly significant increase in cellular aggregates. Finally, although both CCT5 and CCT7 are known to contribute to protein aggregation through autophagy regulation [44], only CCT7, which was shown to interact and affect GPCR aggregation [43], showed an effect in our NPCs.…”

Human Developmental Cell Atlas: milestones achieved and the roadmap ahead

“…There is mounting evidence that disorders identified in childhood and adulthood may have their origins and manifestations during early development (Figure 4). These include structural birth defects [111][112][113][114] , neurodevelopmental disorders including Huntington's disease 115 Moreover, many adult cancers recapitulate a grotesque version of human developmental programs 124 . Conversely, molecular processes that guide human development can be understood by studying developmental disorders 125 , many with significant individual and public health impacts.…”

Abnormal Brain Development in Huntington’ Disease Is Recapitulated in the zQ175 Knock-In Mouse Model

“…Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the huntingtin gene ( HTT ), which encodes an expanded polyglutamine stretch in the huntingtin protein (HTT). Cumulative cellular and molecular studies have demonstrated that brain developmental abnormalities may be a substrate for impaired brain function and later neurodegeneration in HD ( Mehler and Gokhan 2000 ; Reiner et al 2003 ; Cattaneo et al 2005 ; Godin et al 2010 ; Molina-Calavita et al 2014 ; Conforti et al 2018 ; Wiatr et al 2018 ; Barnat et al 2020 ). The HD brain pathology may therefore represent, at least partially, the consequences of abnormal development.…”