Huntington’s disease, like most neurodegenerative conditions, strikes adults. Yet children who carry the infamous causative triple repeat expansion have slightly smaller brains than noncarriers even while they are as functional as their noncarrying siblings, suggesting there could be subtle developmental effects. Supporting this idea, the mutant protein affects embryonic brain development in animal models. In the July 16 Science, researchers led by Sandrine Humbert at INSERM in Grenoble, France, and Alexandra Durr at Sorbonne University in Paris for the first time demonstrate prenatal effects of mutant huntingtin in the human brain. Examining tissue taken from four 13-week-old human fetuses that had inherited the huntingtin gene expansion, they found neural progenitor cells to be abnormal in ways that would likely cause the cells to differentiate too soon, depleting the progenitor pool. This might result in fewer neurons being born.
- In the developing human brain, mutant huntingtin results in the loss of neural progenitor cells.
- This could cause fewer neurons to be born, and explain smaller brain volume in carriers.
- Progenitor cells also were abnormal in their organization, polarity, and endosomal trafficking.
“This is the first direct proof that developmental defects occur in a late-onset neurodegenerative disorder such as Huntington’s disease,” Humbert told Alzforum. The brain appears able to compensate for these abnormalities for decades, however, because carriers remain cognitively healthy until midlife. “By studying how the brain compensates, we may discover new therapeutic targets,” Humbert noted.
“This elegant study extends the previous notion that neurodegenerative disorders are preceded by a long, clinically silent phase of at least several decades that might perhaps even start very early in life,” Marlene Jimenez-Del-Rio of Universidad de Antioquia, Medellin, Colombia, wrote to Alzforum (full comment below). Jimenez-Del-Rio studies autosomal-dominant Alzheimer’s caused by the E280A mutation in presenilin 1, and recently developed a cellular model derived from umbilical cords of newborn mutation carriers (May 2020 news).
Huntington’s disease is caused by an expansion of a CAG repeat in the huntingtin gene. Wild-type huntingtin protein has numerous functions, including helping ferry vesicles along microtubules, regulating cell division and cilia formation, and promoting adhesion of neuroepithelial cells (for review, see Saudou and Humbert, 2016; Lo Sardo et al., 2012).
Mice lacking huntingtin lose forebrain neurons and die in utero (Zeitlin et al., 1995; Reiner et al., 2003). Humbert’s group previously found that mutant huntingtin has similar effects, depleting progenitor cells, derailing migration of newborn neurons, and saddling mice with a thinner cortex (Godin et al., 2010; Barnat et al., 2017; Molina-Calavita et al., 2014).
What about people? Some HD carriers use prenatal genetic testing to avoid passing on this terrible disease to their children. After chorionic villus sampling at 13 weeks revealed the presence of the mutation, four families chose to terminate these pregnancies and to donate the tissue to the authors for research on Huntington’s disease. All four fetuses carried expansions of about 40 repeats, roughly double the normal amount. Humbert and colleagues compared their brains to those from four healthy fetuses from pregnancies terminated for other reasons. Neurodegenerative disease researchers rarely have the opportunity to study such tissue.
In brain slices from the aborted fetuses, first author Monia Barnat examined neural progenitor cells in the ventricular zone. Immunostaining revealed that mutant huntingtin (Htt) appeared stuck at the apical surface of the zone, whereas the wild-type protein was distributed evenly throughout. In addition, mutant Htt misdirected several adhesion proteins, such as ZO1, N-cadherin, and β-catenin, to the apical surface, as well.
Normally these proteins are distributed throughout the ventricular zone, linking progenitor cells together (see image above right). The net effect would likely be to disrupt the close cell contacts and organization of the healthy brain, the authors noted.
At 13 weeks, a still-early stage of human fetal development, progenitor cells are generating the cortical neurons that project to the striatum a few weeks later and, decades later, degenerate in Huntington’s. To do this, their cell bodies migrate between the apical (or ventricular) surface, where they divide, and the basal surface, where they duplicate their DNA. This migration helps maintain the balance between proliferation and differentiation.
In carriers, apical progenitor cells had more cilia than in controls, implying they spent more time at the apical surface and less time on DNA synthesis. This may favor neuronal differentiation over proliferation (Arai et al., 2011). Moreover, there were fewer dividing cells in carriers than in controls, indicating a smaller progenitor pool (see image at left). Progenitor cells looked abnormal in other ways as well. For example, proteins involved in endosomal transport were mislocalized, implying disruptions in trafficking (see image below).
To explore these hints gleaned from human tissue more deeply in an experimental system, the authors turned to a mouse HD model that carries 111 CAG repeats in the huntingtin gene. Brain slices from 13.5-day-old embryos, the equivalent of 13 weeks of gestation in humans, replicated the changes seen in human tissue. Time-lapse imaging of cortical slices confirmed a slowdown in the cycling of progenitor cells, with less time spent in DNA synthesis. As in human tissue, there were fewer dividing cells, revealing a depletion of progenitors.
Altogether, the findings hint at an HD brain unable to generate a normal number of cortical neurons in certain areas. Previous research has found that children carrying 39 or more CAG repeats have smaller brains on average than noncarriers; the study did not break this down by brain region (Lee et al., 2012). However, other factors, such as a loss of dendritic arborization, could explain these smaller brain volumes as well, Humbert noted.
Despite these developmental abnormalities, the brain appears able to compensate. Sarah Tabrizi at University College London recently found that young adult HD carriers are cognitively normal. So is their connectivity between the cortex and striatum, although their striata themselves were slightly smaller than those of controls (Scahill et al., 2020). “[T]hey develop normally and function at a high level into adulthood, until the tipping point when gradual neurodegeneration occurs,” Tabrizi wrote to Alzforum (full comment below).
In Alzheimer’s disease as well, some evidence suggests pathobiology could be related in part to developmental effects of the implicated genes, Dennis Selkoe at Brigham and Women’s Hospital, Boston, wrote to Alzforum. Previously, Selkoe and Tracy Young-Pearse at BWH found that amyloid precursor protein is required for neural precursor cells to migrate to the correct position in the cortical plates of embryonic mice (Young-Pearse et al., 2007).
Eric Reiman and colleagues at Banner Alzheimer’s Institute in Phoenix have associated familial APP mutations with hypometabolism and white-matter loss in mice (Gonzalez-Lima et al., 2001; Valla et al., 2008). Children who carry the Paisa presenilin mutation show functional abnormalities on fMRI when performing cognitive tasks, suggesting their brains work less efficiently (Dec 2011 conference news; Jul 2015 news). Some APOE4 carriers have deficits in gray and white matter even as babies, as well as sluggish brain glucose metabolism and subtle problems with their spatial navigation as young adults (Dean et al., 2014; Reiman et al., 2004; Oct 2015 news).
“Evidence of neurodevelopmental effects does raise questions about just how early treatments need to be started in order to be effective,” Nick Fox at UCL wrote to Alzforum. Tabrizi noted that disease-modifying therapies for HD and other neurodegenerative disorders should start as early as possible. Fox agreed, but also noted that people with familial AD mutations are clinically indistinguishable from noncarriers until quite close to symptom onset. “[That] means that there is still great potential for therapies to have a transformative impact even at this stage,” Fox wrote (full comment below).—Madolyn Bowman Rogers
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