Unmet needs in hyperkinetic movement disorders (HMDs) within neuropsychiatric conditions include better treatments for HMDs in complex disorders like Huntington's disease (HD), Tourette syndrome and psychiatric comorbidities like tardive dyskinesia. The symptomatology of HD comprises chorea, a disabling movement disorder, neuropsychiatric disturbances and cognitive decline. VMAT2 inhibitors like tetrabenazine and its derivatives, as well as antipsychotics, are used for the treatment of HMDs but they may worsen motor function or the underlying neuropsychiatric symptoms. Specifically targeted therapies improving management of motor and non-motor symptoms with a safety profile suited for continued chronic treatment are needed. We describe here the novel mechanism of action of SOM3355, a CNS-permeant selective β1-blocker (bevantolol) found to have additional VMAT2 and VMAT1 modulation activity. SOM3355 is a clinical drug candidate for the treatment of HD that has shown positive clinical effects in the motor-behavioral/psychiatric-cognitive symptom triad characteristic of the disease. In vitro and in vivo studies were conducted to evaluate SOM3355's inhibitory activity at VMAT1, VMAT2 and CNS targets. Functional uptake and radioligand binding assays were performed in rat vesicles and human recombinant systems. SOM3355 inhibited VMAT2-mediated dopamine uptake comparably to tetrabenazine but displayed markedly lower affinity for the α-dihydrotetrabenazine binding site, suggesting a distinct interaction mode. Unlike tetrabenazine, SOM3355 potently inhibited VMAT1, a vesicular monoamine transporter present in different brain areas and implicated in neuropsychiatric regulation. Additionally, SOM3355 exhibited negligible off-target CNS binding, consistent with the favorable CNS safety profile observed in clinical trials. By combining synergistic β1-adrenergic antagonism, VMAT2-mediated dopamine modulation, and VMAT1 inhibition, SOM3355 may address monoamine neurotransmitter imbalances within basal ganglia and cortical circuits involved in motor and neuropsychiatric manifestations of HD. In summary, the translational profile of SOM3355, aligned with its clinical evaluation to date, supports its positioning as a potential novel therapeutic alternative for the treatment of HMDs and neuropsychiatric conditions like HD, tardive dyskinesia and Tourette Syndrome.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded cytosine-adenine-guanine (CAG) repeat (> 36 repeats) in the huntingtin gene, leading to progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Despite extensive research, the precise pathophysiological mechanisms underlying HD remain incompletely understood, necessitating reliable experimental models to investigate disease processes and identify therapeutic targets. Among preclinical models, 3-nitropropionic acid (3-NPA) is widely used to induce HD-like pathology in neuronal cell lines and animal models, including rats, mice, zebrafish, and avian species. In this review, we comprehensively discuss the molecular mechanisms underlying 3-NPA-induced neurotoxicity and its relevance to HD. 3-NPA primarily exerts its effects by irreversibly inhibiting succinate dehydrogenase (SDH), leading to mitochondrial dysfunction and energy failure. This metabolic disruption triggers oxidative stress, excitotoxicity, calcium dysregulation, and neuroinflammation, ultimately leading to selective striatal neurodegeneration and HD-like behavioral abnormalities. In addition to central nervous system effects, we also summarize the peripheral toxicities associated with 3-NPA, including skeletal muscle wasting, renal and hepatic dysfunction, ovarian stress, and cardiotoxicity. While 3-NPA effectively recapitulates several key pathological features of HD, it does not reproduce mutant huntingtin aggregation or progressive disease progression, representing a major limitation of this model. Overall, 3-NPA-induced pathology serves as a valuable experimental tool for studying specific aspects of HD, particularly mitochondrial dysfunction and related downstream pathways. Future studies integrating metabolic and genetic models will be essential to achieve a more comprehensive understanding of HD pathogenesis and to facilitate the development of effective therapeutic strategies.

Huntington's disease (HD) is an enormously destructive autosomal hereditary neurodegenerative disease that results in malfunction of motor, psychological, and cognitive deficits. The neurotoxin 3-nitropropionic acid (3-NPA) is known to induce HD-like signs in the in vivo rat model. The current research is aimed at defining the defensive properties of pinostrobin (PSB) against 3-NPA-induced HD in rats. Wistar rats were used as a test model, and PBS (10, 20, and 40 mg/kg, per oral) was administered before 3-NPA (10 mg/kg i.p.) treatment for 15 days. To assess neurodegeneration, behavioural tests such as the narrow beam walk, rotarod test, open field test, and grip strength test were performed. The effect of PSB on 3-NPA induced alterations on lipid peroxidation and oxidative stress markers (malondialdehyde, superoxide dismutase, reduced glutathione, and catalase), neurotransmitter levels (dopamine serotonin, glutamate, and GABA), Complex I (ATP generation) and Complex II (succinate dehydrogenase) cytokines levels (tumour necrosis factor-α, interleukin-1β, and IL-6), programmed cell-death marker levels (Caspase-3 and Caspase-9), and brain-derived neurotrophic factor (BDNF) was assessed by brain striatum homogenate. In silico analyses, including molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, principal component analysis, dynamic cross-correlation mapping, and free energy landscape profiling, were conducted to clarify the molecular interactions between PSB and relevant HD-related targets. Results showed that the 3-NPA-induced group of rats had significantly decreased behavioural activity, oxidative stress, neurotransmitter levels, and neuroinflammatory indices. Treatment with PSB improves cognitive functions, increases antioxidant marker levels, modulates inflammatory marker expression, and provides neuroprotection against the tested neurotoxin. Computational analyses, including MD, molecular dynamics, and MM-GBSA free energy profiling, demonstrated favourable binding affinity of PSB with target proteins involved in SDH and BDNF. Thus, PSB may be a promising neuroprotective candidate for managing 3-NPA-induced brain dysfunction and cognitive deficits, which are similar to those observed in Huntington's disease.

Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulating autophagy. However, it is still elusive which protein is UFMylated and how this modification modulates autophagy. Here, our quantitative proteomics and biochemical experiments identify SQSTM1/p62 as a UFMylation substrate and discover its two major UFMylation sites, K420 and K435. Mutating them to Arg (p62[2KR]) completely abolishes the effect of p62 on autophagic activity. Fusion of UFM1[ΔC4] to p62[2KR] (p62[2KR]-UFM1[ΔC4]) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.

Transposable elements (TEs) are implicated in aging and neurodegenerative disorders, but the impact on brain TE RNA dynamics in these phenomena is not fully understood. Therefore, we quantify TE RNA changes in aging postmortem human and mouse brains and in the neurodegenerative disorders Huntington's disease (HD) and Parkinson's disease (PD). We track TE small RNAs (smRNAs) to assess the relationship to TE large RNA (laRNA) expression patterns. Human brain transcriptomes from the BrainSpan Atlas display significant shifts of TE smRNA patterns, whereas aging mouse brains lack any TE RNA changes despite a clear shift in aging-associated gene messenger RNA (mRNA) levels. The human frontal cortex displays the most pronounced sense TE smRNAs with a negative relationship between the TE smRNAs and laRNAs indicative of age-associated regulatory effects. Our analysis reveals TE smRNA dysregulation in HD, whereas PD shows a stronger impact on TE laRNAs, potentially correlating with the early average age of death for HD relative to PD. Furthermore, the TE-silencing factor TRIM28 is downregulated in adult human brains, possibly explaining some of these observed TE RNA changes. Our study suggests that the expression of particular TE RNAs may serve as biomarkers of human brain aging and neurodegenerative disorders.

The hypothesis that Group A beta-haemolytic Streptococcus (GAS) triggers an autoimmune cascade targeting basal ganglia dopaminergic circuits-producing obsessive-compulsive disorder (OCD), tic disorders, or chorea depending on the receptor subtype involved-is biologically compelling and supported by emerging molecular evidence. Yet PANDAS has remained a diagnostic conundrum since its original description in 1998, with ongoing uncertainty surrounding diagnostic criteria, the interpretation of streptococcal serology, and the distinction from primary neurodevelopmental disorders. This study aimed to review the diagnostic challenges of PANDAS, with focus on streptococcal serology interpretation, advances in dopamine receptor autoantibody biology, the genetic epidemiology of primary tic disorders, and the differential diagnosis of acute neuropsychiatric presentations in children. A structured narrative review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Library for publications from 1998 to early 2025 addressing PANDAS, PANS, streptococcal antibodies, childhood movement disorders, autoimmune encephalitis, and the genetics of tic disorders. No currently available biomarker-including ASO, anti-DNase B, anti-basal-ganglia antibodies, or the Cunningham Panel-has demonstrated adequate individual-level diagnostic accuracy for PANDAS. Emerging molecular evidence identifies anti-D1R autoantibodies, acting via G protein-and beta-arrestin-mediated signalling, as candidate biomarkers for PANDAS/PANS neuropsychiatric phenotypes, and anti-D2R autoantibodies for Sydenham chorea movement phenotypes; independent replication in unselected populations is required. Primary tic disorders carry heritability estimates of 50-80% and first-degree familial risk ratios of approximately 18-fold in large population-based cohorts. Prospective blinded studies have not demonstrated a consistent population-level association between GAS infections and tic or OCD exacerbations: PANDAS and PANS remain diagnoses of exclusion. The high background prevalence of both GAS exposure and primary neurodevelopmental disorders in overlapping paediatric age ranges creates conditions for incidental temporal co-occurrence. In the absence of validated molecular biomarkers, diagnostic imprecision carries direct clinical consequences: children may be exposed to treatments with significant risk profiles-including IVIG, plasma exchange, and prolonged antibiotic prophylaxis-while evidence-based therapies are delayed. A stepwise diagnostic approach incorporating the full differential diagnosis is both an epistemological and a patient safety imperative.

Huntington's disease is caused by a CAG expansion in the HTT gene, leading to somatic repeat instability, alternative processing of HTT pre-mRNA, and mutant huntingtin protein production. To model these features, we generated a knock-in minipig (KI-85Q-HD) carrying a (CAG)82CAA(CAG)2 repeat in the endogenous HTT locus. To evaluate this, we quantified somatic expansion in various tissues using small pool- and bulk-PCR; detected HTT1a, an aberrantly spliced HTT transcript, using 3' rapid amplification of cDNA ends and quantitative PCR; and assessed mutant huntingtin protein isoforms using homogeneous time-resolved fluorescence assays. Moderate levels of tissue-specific and age-dependent somatic expansion were observed, highest in the caudate nucleus, kidney and spleen, and detectable in blood cells. We confirmed the presence of HTT1a transcripts terminating at a cryptic polyadenylation site in HTT intron 1, and detected soluble full-length mutant HTT and HTT1a proteins across brain regions and peripheral tissues, while aggregated HTT1a was only detected in the cortex. These results indicate that KI-85Q-HD minipigs exhibit molecular features of Huntington's disease at a pre-symptomatic stage and may serve as a platform for assessing therapeutic distribution and potency.