A neuroglial framework for HD is defined that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration.
Abstract
Huntington’s disease (HD) has traditionally been conceptualized as a neuron-centric disorder primarily attributed to cell-autonomous toxicity of mutant huntingtin (mHTT) in striatal medium spiny neurons. However, this framework inadequately explains the prolonged presymptomatic phase, selective network vulnerability, early non-motor manifestations, and limited success of neuron-targeted therapeutic interventions. Accumulating evidence from molecular biology, transcriptomics, neuroimaging, and preclinical therapeutics supports a reframing of HD as a disorder of neuroglial systems dysfunction. We synthesize data demonstrating that astrocytes, microglia, and oligodendrocyte lineage cells are not passive bystanders but play direct and interactive roles in HD pathogenesis through defined molecular mechanisms. Expression of mHTT in glial populations impairs synaptic homeostasis, metabolic coupling, immune resolution, and myelin integrity, generating self-amplifying pathological feedback loops that destabilize neural circuits long before overt neuronal death. Critically, we evaluate glial replacement therapy as a potential disease-modifying strategy. Preclinical studies demonstrate that transplantation of healthy human glial progenitor cells substantially ameliorates motor, cognitive, and neuropathological deficits in multiple HD models through oligodendroglial remyelination and lactate-mediated metabolic support, despite persistent neuronal mHTT expression. Effective HD therapy will likely require strategies that jointly target the genetic cause and the dysfunctional neuroglial microenvironment. By integrating systems neuroscience with glial biology and translational strategy, this review defines a neuroglial framework for HD that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration.
Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin gene (HTT), resulting in mutant huntingtin (mHTT) with toxic gain-of-function and partial loss of normal huntingtin function. This narrative review summarizes recent advances in genetics, pathophysiology, clinical features, diagnostic assessment, biomarkers, and therapeutic development. Genetic testing demonstrating an expanded HTT CAG repeat is the definitive diagnostic test and should be interpreted with genetic counseling and attention to allele categories. Pathophysiologically, HD involves CAG instability, age-dependent somatic expansion in vulnerable neurons, transcriptional dysregulation, proteostasis failure, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, leading primarily to degeneration of striatal medium spiny neurons and later cortical involvement. Clinically, HD can begin from juvenile to late-adult life and manifests with motor, cognitive, psychiatric, and behavioral symptoms that evolve from premanifest biological change to functional decline. Current clinical care relies on symptom-directed treatment, whereas quantitative neuroimaging, cerebrospinal fluid biomarkers are mainly used for research and trial enrichment. Symptomatic management includes vesicular monoamine transporter type 2 inhibitors, antipsychotics, rehabilitation, nutritional support, and multidisciplinary care. Emerging disease-modifying approaches include HTT-lowering, somatic expansion inhibition, and gene-based therapies, but efficacy depends on target selectivity, timing, delivery route, dose, and patient selection.
A. Cervantes-Arriaga, Ashley Xanat Beltrán-Torres, Diego Romero-García et al.· Revista de investigacion cli...· 0 citations
Depression affects Huntington's disease (HD) gene-expansion carriers at up to four times the general population rate, yet its neurobiological underpinnings remain inadequately understood, potentially contributing persistent symptoms and suboptimal therapeutic outcomes despite commonly used interventions. Understanding the pathophysiological mechanisms remains constrained by fragmented, single-level approaches that do not capture interactions between biological systems. Here, we present an illustrative multilevel, reciprocal pathophysiological framework that integrates evidence across brain network (macro), neurotransmitter (meso), and molecular and systemic (micro) scales that contribute to depression vulnerability in HD. We highlight available evidence suggesting HD-related neurobiological changes contribute to depression. Preferential vulnerability of GABAergic medium spiny neurons in HD may contribute to dysfunction across cortico-basal-ganglia-thalamic circuits, interacting with cellular, molecular, and systemic processes. At the macro level, altered neurocircuitry is represented by structural changes and functional dysconnectivity across brain networks. The meso level represents cellular and neurotransmitter alterations, including glutamatergic, serotonergic, and dopaminergic dysregulation. At the micro level, molecular and systemic alterations include neuroendocrine, immune, neurotrophic, and gut microbiota-brain axis processes. We discuss how this reciprocal framework provides a foundation for generating testable hypotheses regarding the mechanisms underlying depression in HD and highlight future research priorities, including improved psychiatric phenotyping, longitudinal multimodal study designs, cross-species behavioral harmonization, and integration of behavioral, circuit-level, molecular, and systemic measures.
Tamrin Barta, Y. Glikmann-Johnston, P. McColgan et al.· Neuroscience and Biobehavior...· 0 citations
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. While neuronal dysfunction has traditionally been the focal point of PD research, growing evidence highlights the critical roles of astrocytes - the most abundant glial cells in the central nervous system - in PD pathogenesis and therapy. Targeting astrocytes offers a promising therapeutic avenue through astrocyte-to-neuron reprogramming, inducing A2 phenotypic polarization, suppressing oxidative stress, modulating metal ion deposition, enhancing neurotransmitter homeostasis and promoting α-synuclein clearance. These diverse roles enable astrocytes to act as both protectors and potential contributors to disease progression, depending on the cellular environment. Furthermore, innovative strategies such as gene therapy, nanoparticle-based drug delivery, and astrocyte-derived exosome systems hold potential to overcome barriers like the blood-brain barrier and offer targeted, multifactorial interventions. Collectively, these findings advocate for a paradigm shift from a neuron-centric to a glia-inclusive framework in PD research and treatment, positioning astrocytes as central players in the quest for disease-modifying therapies.
Shuang Wu, Wenjun Wang, Linlin Yang et al.· Experimental Neurology· 0 citations
The urgent need for reliable biomarkers, early diagnosis, and multidisciplinary disease-modifying strategies for future therapeutic interventions is highlighted, with particular emphasis on challenges associated with bench-to-bedside translation.
Jeewanjot Singh, Subhi Sharma, Prabhjot Singh et al.· Advances in Modern Biomedici...· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
Background: Parkinson’s disease (PD) exhibits remarkable clinical heterogeneity, with substantial variability in motor progression, cognitive decline, and the development of non-motor manifestations. Although the propagation of pathological alpha-synuclein is considered a central mechanism of PD pathogenesis, it does not fully explain why specific neuronal populations demonstrate differential susceptibility to degeneration. Emerging evidence suggests that selective neuronal vulnerability is determined by the interaction of multiple biological domains, including calcium homeostasis, mitochondrial bioenergetic capacity, lysosomal function, axonal architecture, synaptic resilience, and neuroinflammatory responses. Methods: A structured critical narrative review was performed using PubMed/MEDLINE, Scopus, and Web of Science databases from inception to March 2025. Only full-text articles published in English and peer-reviewed journals were included. Evidence from human post-mortem studies, genetic analyses, biomarker investigations, experimental models, induced pluripotent stem cell studies, and longitudinal clinical cohorts were systematically synthesised to identify the principal mechanisms underlying selective neuronal vulnerability and their potential translational application. To capture evidence published after this electronic cut-off, a supplementary manual review of reference lists of key systematic reviews and landmark publications was conducted up to the date of manuscript submission; references with 2025 or 2026 publication dates entered through this supplementary process. The supplementary manual review was conducted as a targeted scan of reference lists of key systematic reviews and high-impact publications identified during the primary search and did not constitute an independent updated systematic search. Results: Five interconnected biological domains emerged as key determinants of neuronal susceptibility in PD: calcium-mediated metabolic stress associated with autonomous pacemaker activity, mitochondrial dysfunction and energetic failure, impaired lysosomal degradation and proteostasis (particularly involving the GBA1–glucocerebrosidase pathway), vulnerability related to extensive axonal and synaptic architecture, and neuroinflammatory mechanisms involving microglial and astrocytic activation. Among these domains, the lysosomal pathway currently provides the strongest translational link between molecular mechanisms and measurable clinical outcomes. Based on this integrated framework, we propose the Parkinson’s Vulnerability Index (PVI), a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials. Conclusions: Selective neuronal vulnerability provides a complementary framework to alpha-synuclein propagation models for understanding the heterogeneity of PD. The proposed PVI is not intended as a diagnostic or prognostic clinical instrument but as a research tool requiring prospective validation. Future precision medicine approaches in PD may benefit from integrating vulnerability-related biomarkers with existing biological staging systems to identify patients most likely to benefit from targeted disease-modifying therapies.
Livia Livinț-Popa, Andreea Nicolaie, A. Maștaleru et al.· Medical Science· 0 citations