Abstract
The classic concept of the pathoetiology of Huntington's disease (HD) is a toxic gain-of-function process by which mutant huntingtin (mHTT) directly causes neuronal cell death. However, over the past two decades, increasing evidence has highlighted the important role that brain development may play in the etiology of HD. This special edition of the Journal of Huntington's Disease assembles a series of expert reviews examining the role of neurodevelopment in HD. Together, these contributions highlight the diverse methodological approaches and emerging conceptual frameworks that are reshaping how the field understands the developmental origins of the disease.
One of the most prominent factors motivating theories of neurodevelopment in HD is that HTT is essential for normal brain development. This observation provides the foundation for investigating both the physiological functions of wild-type HTT in normal brain development, and the ways in which these processes are altered by the mutant HTT allele. Chan and Leavitt explore wild-type HTT's putative function, expression, and variation in neurodevelopment in the absence of the mutant HTT allele, providing an important framework for understanding how alterations in wild-type HTT function may contribute to human health and disease. Their review highlights the broad involvement of HTT in neurodevelopmental processes such as ciliogenesis, neurogenesis, intracellular transport, and synaptic maturation. Shin and Hefti also examine the roles of HTT and mHTT in development, drawing on comparative evolutionary analyses and the concept that HTT may represent a gene exhibiting antagonistic pleiotropy—the paradox of both ability and liability, in which advantageous developmental processes may ultimately be linked to later neurodegeneration. Their review further emphasizes that HTT participates in neuronal migration, synaptogenesis, apoptosis regulation, and mitotic spindle orientation, suggesting that both loss- and gain-of-function mechanisms may influence early brain development.
Because neurodevelopment can be conceptualized broadly, several of the reviews in this issue focus on specific methodologies that have been used to explore the connections between development and degeneration. Altun et al. examine how various HD mouse models have revealed distinct, yet frequently converging, developmental abnormalities arising from the interplay of early pathogenic and homeostatic processes. Across transgenic, knock-in, and loss-of-function models, early alterations include impaired neural progenitor dynamics, glial dysfunction, corticostriatal synaptic deficits, and disrupted circuit formation, suggesting that early-life circuit miswiring may predispose the brain to later neurodegeneration. Given the growing power of stem cell–derived models, Sierra et al. review advances in both 2D and 3D model systems, from differentiated monocultures to brain-like organoids and assembloids, and how these platforms have expanded our understanding of HD-associated phenotypes. These models reveal early developmental perturbations, including altered neural progenitor polarity, disrupted ciliogenesis, transcriptional dysregulation, and defects in neuronal migration and cortical organization. Schultz and Nopoulos review findings from human imaging studies of children at risk for HD, revealing early-life differences in brain structure and function consistent with a developmental advantage. Integrating longitudinal data from cohorts such as Kids-HD and ChANGE-HD with evolutionary theories of antagonistic pleiotropy, they propose that early developmental benefits may come at the cost of accelerated aging and neurodegeneration. Specifically, mHTT may promote early cortical expansion and improved cognitive performance while increasing vulnerability to later striatal degeneration through mechanisms including glutamatergic excitotoxicity and metabolic stress. Thus, mHTT may initially conferr a developmental advantage - reflected in a larger, more metabolically active cortex - while simultaneously predisposing the brain to later excitotoxicity, energy imbalance, and cellular degeneration. Finally, Scuto et al. highlight how epigenetic and transcriptional alterations occurring during neural differentiation may shape neuronal specification and maturation. They propose that abnormal developmental epigenetic priming may predispose vulnerable neuronal populations - particularly striatal spiny projection neurons - to later transcriptional dysregulation and epigenetic erosion, accelerating neuronal aging and degeneration.
Although degeneration of the striatum is central to the clinical manifestations of HD, the cerebral cortex plays a critical role in the context of neurodevelopment. Two articles in this issue examine how alterations in cortical development may influence later disease processes. Cepeda et al. present an in-depth examination of recent findings from genetic animal models demonstrating how developmental changes in cortical circuitry, and the resultant cortical hyperexcitability, may contribute to HD pathophysiology. Their review highlights evidence that disrupted corticogenesis, neuronal migration, and cortical architecture lead to hyperexcitable cortical networks that place excessive excitatory drive on striatal neurons. Degennaro et al. provide an overview of both in vitro and in vivo studies highlighting the molecular mechanisms through which HTT and mHTT influence developmental processes, with particular attention to the cerebral cortex. They describe the role of HTT from early embryogenesis - including gastrulation and neurulation - to later stages of cortical maturation, emphasizing the importance of gene dosage and intracellular transport mechanisms.
HD cannot be understood solely as a disorder of late-life neurodegeneration, but must also be considered within the context of brain development. Yet important questions remain unresolved. Much of the experimental work in non-human systems frames HD as a disorder of abnormal neurodevelopment, suggesting that early developmental aberration establish the substrate upon which later degeneration unfolds. In contrast, insights from evolutionary biology regarding HTT function, as well as the human studies that have directly examined neurodevelopment in children at risk for HD, have revealed patterns more consistent with developmental advantage rather than developmental aberration. Reconciling these divergent observations represents a central challenge for the field. These differences may reflect species-specific biology, methodological limitations, or a more complex developmental trajectory of HTT function than is currently appreciated. Alternatively, they may reflect a matter of semantics, in which developmental changes are often labeled as “abnormal” when it remains unclear whether those changes confer ability, liability, or both.
Additionally, therapeutic strategies aimed at lowering mutant huntingtin (mHTT) protein levels have become a central focus of drug discovery efforts in HD. However, reducing the expression of a gene that plays an essential role in brain development must be approached with considerable caution, particularly given the prolonged trajectory of human brain maturation, with important developmental processes continuing into the third decade of life. Although current clinical studies typically target individuals early in the course of disease, the ultimate goal is to develop interventions capable of preventing HD altogether. Whether lowering mHTT expression would ultimately prevent the disease, however, remains unknown. A deeper understanding of the developmental biology of HD will be critical for determining both the potential impact of mHTT-lowering strategies and the optimal developmental window during which such interventions might be most effective.
As the contributions in this special issue illustrate, understanding how mutant HTT shapes the developing brain—and how those early processes relate to the long premanifest course of the disease—remains one of the most important frontiers in Huntington's disease research.
