Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene. Existing toxin-induced and genetic models provide important insights, but none fully replicate the progressive pathology of HD. An AAV9-mediated striatal mouse model expressing mutant HTT with 82 CAG repeats was established to reproduce hallmark neuropathological changes and behavioral deficits. Male C57BL/6 mice received bilateral intrastriatal injections of AAV9-HTT-82Q or control AAV9-GFP. Behavioral performance was assessed by rotarod, balance beam, open field, and Y-maze tests. Neuropathology was examined with HE/Nissl staining, TUNEL assay, and immunofluorescence for mHTT, DARPP-32, GFAP, and Iba1. AAV9-82Q mice exhibited progressive motor coordination deficits on the rotarod from Week 4 and impaired beam traversal from Week 18. Open field testing revealed persistent hyperactivity from Week 8, while anxiety-like and cognitive measures showed only mild, non-significant trends. Histological analysis demonstrated extensive mHTT aggregation in the striatum, accompanied by neuronal pyknosis, vacuolization, and significant loss of Nissl-positive neurons. TUNEL staining confirmed increased apoptosis. Immunofluorescence further revealed selective reduction of DARPP-32+ medium spiny neurons, along with marked astrogliosis and microgliosis, indicating robust neurodegeneration and inflammatory responses. The AAV9-82Q model induces adult-onset, progressive HD-like pathology with early motor impairments, neuronal loss, and glial activation. It complements existing models and provides a reproducible platform for mechanistic studies and preclinical therapeutic evaluation.

Huntington's disease (HD) is a hereditary neurodegenerative condition, passed down in an autosomal dominant manner, characterized by the gradual decline of motor functions, such as chorea, along with psychiatric symptoms and cognitive deterioration. In HD, the striatum is the main area impacted, although cerebellar atrophy has also been observed independently of striatal degeneration. Consequently, HD patients may exhibit symptoms consistent with cerebellar cognitive affective syndrome (CCAS) due to cerebellar involvement. CCAS manifestations have been noted in various rodent models of motor dysfunctions linked to cerebellar atrophy. Previous research has identified anxiety, memory deficits, and depressive-like behavior in the YAC128 transgenic murine model of HD. This investigation examines the effects of prolonged administration of the small-conductance calcium-activated potassium channel (SK channel) positive modulator chlorzoxazone (CHZ), both alone and in combination with folic acid (FA), on cerebellar Purkinje cell (PC) electrophysiology and morphology, along with locomotor and memory decline and emotional state changes in YAC128 mice. The findings indicate that both CHZ alone and the mixture of CHZ and FA similarly ameliorated cerebellar-specific deficits, encompassing the precision of PC electrophysiological activity and beam walk performance in YAC128 mice. However, solely the mixture of CHZ and FA significantly alleviated depressive-like symptoms and improved recognition memory. These findings imply that a therapeutic approach addressing both motor and cognitive-affective deficits is essential for the holistic management of movement disorders associated with cerebellar atrophy, including HD.

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by the selective dysfunction and loss of neurons in the striatum and cerebral cortex. Experimental evidence suggests that GABAergic medium-sized spiny neurons (MSNs) in the striatum are particularly vulnerable to glutamate-induced toxicity (excitotoxicity) and its analogues. However, the molecular mechanisms underlying MSN-specific death in HD remain poorly understood. The serine/threonine protein kinase D1 (PKD1) confers neuroprotection in various neuropathological conditions, including ischemic stroke. While excitotoxicity inactivates PKD1 in cortical glutamatergic neurons without altering its levels, active PKD1 potentiates the survival of excitatory neurons in highly excitotoxic environments. Here, we investigated whether PKD1 activity dysregulation contributes to MSN death in HD and its association with neurodegeneration. We found an unexpected reduction in PKD1 protein levels in striatal neurons from HD patients. Similarly, the R6/1 mouse model of HD exhibited progressive PKD1 protein loss, commencing at early disease stages, accompanied by decreased Prkd1 transcript levels. PKD1 downregulation also occurred in the cerebral cortex of R6/1 mice, but only at late stages. Functionally, pharmacological PKD inhibition in primary striatal neurons exacerbated excitotoxic damage and apoptosis induced by glutamate N-methyl D-aspartate (NMDA) receptors, whereas expression of constitutively active PKD1 (PKD1-Ca) conferred neuroprotection. Furthermore, PKD1-Ca protected against polyQ-induced apoptosis in a cellular model of HD. In a translational approach, intrastriatal lentiviral delivery of PKD1-Ca in symptomatic R6/1 mice prevented the loss of DARPP-32, a molecular marker of MSNs. Collectively, our findings strongly suggest that PKD1 loss-of-function contributes to HD pathogenesis and the selective vulnerability of MSNs. These findings position PKD1 as a promising therapeutic target for mitigating MSN death in HD.

"Huntington's disease" (HD) is an autosomal dominant hereditary neurodegenerative disease characterized by defects in efferent striatal neurons, cortical neurons, and the basal ganglia. The pathogenesis of HD is still unclear, and there is currently no curative therapy for this disorder. This review emphasizes the potential beneficial effects of various neurotrophic factors in HD. PubMed, Web of Science, Embase, and google scholar databases were used to search for all studies on the efficacy of neurotrophic factors in HD. Several gene therapy strategies have been employed to treat HD, including gene therapy with a variety of neuroprotective factors. Moreover, a wide variability of gene therapy approaches such as a neurotrophin, has shown promising results for both prevention and neuroprotection in HD, which may be due to their potential to prevent neuronal cell death or decrease neurodegeneration, thereby promoting the growth of innovative axons, dendrites, and synapses leading to improvement of HD. Neurotrophic factors may be suitable as neuroprotective therapy agents in HD. Therefore, substantial research on gene therapy should be conducted to provide better treatment options for HD in the future.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR) > 0.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR = 3.2 × 10-12), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR = 2.6 × 10-3), accompanied by brain atrophy, predominantly in the caudate (FDR = 5.5 × 10-10) and putamen (FDR = 1.2 × 10-9). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR = 0.072) and putamen (FDR = 0.148) atrophy. Atypical loss of interruption HTT repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration: NCT06391619 .