Elevated SLC7A2 expression is associated with an abnormal neuroinflammatory response and nitrosative stress in Huntington's disease.

We previously identified solute carrier family 7 member 2 (SLC7A2) as one of the top upregulated genes when normal Huntingtin was deleted. SLC7A2 has a high affinity for L-arginine. Arginine is implicated in inflammatory responses, and SLC7A2 is an important regulator of innate and adaptive immunity in macrophages. Although neuroinflammation is clearly demonstrated in animal models and patients with Huntington's disease (HD), the question of whether neuroinflammation actively participates in HD pathogenesis is a topic of ongoing research and debate. Here, we studied the role of SLC7A2 in mediating the neuroinflammatory stress response in HD cells. RNA sequencing (RNA-seq), quantitative RT-PCR and data mining of publicly available RNA-seq datasets of human patients were performed to assess the levels of SLC7A2 mRNA in different HD cellular models and patients. Biochemical studies were then conducted on cell lines and primary mouse astrocytes to investigate arginine metabolism and nitrosative stress in response to neuroinflammation. The CRISPR-Cas9 system was used to knock out SLC7A2 in STHdhQ7 and Q111 cells to investigate its role in mediating the neuroinflammatory response. Live-cell imaging was used to measure mitochondrial dynamics. Finally, exploratory studies were performed using the Enroll-HD periodic human patient dataset to analyze the effect of arginine supplements on HD progression. We found that SLC7A2 is selectively upregulated in HD cellular models and patients. HD cells exhibit an overactive response to neuroinflammatory challenges, as demonstrated by abnormally high iNOS induction and NO production, leading to increased protein nitrosylation. Depleting extracellular Arg or knocking out SLC7A2 blocked iNOS induction and NO production in STHdhQ111 cells. We further examined the functional impact of protein nitrosylation on a well-documented protein target, DRP-1, and found that more mitochondria were fragmented in challenged STHdhQ111 cells. Last, analysis of Enroll-HD datasets suggested that HD patients taking arginine supplements progressed more rapidly than others. Our data suggest a novel pathway that links arginine uptake to nitrosative stress via upregulation of SLC7A2 in the pathogenesis and progression of HD. This further implies that arginine supplements may potentially pose a greater risk to HD patients.

The relationship between disease-specific psychosocial stressors and depressive symptoms in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disease involving motor abnormalities, cognitive decline, and psychological difficulties. Depression is among the most common psychological difficulties in HD. People with HD encounter numerous stressors related to their diagnosis and the impact of HD on their daily lives. Understanding the relationship between HD-specific psychosocial stressors and depression symptoms is critical for optimising treatment and developing a holistic, disease-specific model of depression in HD. METHODS: Fifty-seven adults with the HD gene expansion (33 pre-symptomatic, 24 symptomatic) completed a self-report depression questionnaire and rated how much stress they experienced in relation to 20 psychosocial challenges commonly associated with HD. We examined associations between depression symptoms and each stressor individually, and after clustering using principal components analysis. RESULTS: Depression symptoms were significantly associated with most of the psychosocial stressors assessed. Clustering with principal components analysis revealed that higher depression scores had significant independent associations with greater stress related to the future implications of HD (ß = .44, p = .001) and sleep and psychological difficulties (ß = .28, p = .005), but not with stress related to functional limitations (ß = .11, p = .33) or interpersonal issues caused by HD (ß = .15, p = .21). CONCLUSIONS: Stressful experiences associated with HD constitute an important risk factor for depression in HD. Our findings support the use of more psychologically informed models of depression in HD and necessitate further research on tailored psychosocial interventions for HD patients with depression.

Hypertension, antihypertensive drugs, and age at onset of Huntington's disease.

BACKGROUND: Associations between blood pressure (BP) with age at onset of Huntington's disease (HD) have reported inconsistent findings. We used Mendelian randomization (MR) to assess effects of BP and lowering systolic BP (SBP) via the genes encoding targets of antihypertensive drugs on age at onset of HD. METHODS: Genetic variants from genome-wide association studies(GWAS) of BP traits and BP-lowering variants in genes encoding antihypertensive drugs targets were extracted. Summary statistics for age at onset of HD were retrieved from the GWAS meta-analysis of HD residual age at onset from the GEM-HD Consortium included 9064 HD patients of European ancestry (4417 males and 4,647 females). MR estimates were calculated using the inverse variance weighted method, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. RESULTS: Genetically predicted SBP or diastolic BP increase was associated with a later age at onset of HD. However, after SBP/DBP was present as a covariate using multivariable MR method, no significant causal association was suggested. A 10-mm Hg reduction in SBP through variants in genes encoding targets of calcium channel blockers (CCB) was associated with an earlier age at onset of HD (ß=-0.220 years, 95% CI =-0.337 to -0.102, P = 2.42 × 10- 4). We did not find a causal association between angiotensin converting enzyme inhibitors and ß-blockers with the earlier HD onset. No heterogeneity and horizontal pleiotropy were identified. CONCLUSIONS: This MR analysis provided evidence that genetically determined SBP lowering through antihypertensive drugs might be associated with an earlier age at onset of HD. The results may have a potential impact on management of hypertension in the pre-motor-manifest HD population.

Dynamic Covalent Template-Guided Screen for Nucleic Acid-Targeting Agents.

Trinucleotide repeat diseases such as myotonic dystrophy type 1 (DM1) and Huntington's disease (HD) are caused by expanded DNA repeats that can be used as templates to synthesize their own inhibitors. Because it would be particularly advantageous to reversibly assemble multivalent nucleic acid-targeting agents in situ, we sought to develop a target-guided screen that uses dynamic covalent chemistry to identify multitarget inhibitors. We report the synthesis of a library of amine- or aldehyde-containing fragments. The assembly of these fragments led to a diverse set of hit combinations that was confirmed by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) in the presence of DM1 and HD repeat sequences. Of interest for both diseases, the resulting hit combinations inhibited transcription selectively and in a cooperative manner in vitro, with inhibitory concentration (IC50) values in the micromolar range. This dynamic covalent library and screening approach could be applied to identify compounds that reversibly assemble on other nucleic acid targets.

Environmental stimulation in Huntington disease patients and animal models.

While Huntington disease (HD) is caused solely by a polyglutamine expansion in the huntingtin gene, environmental factors can influence HD onset and progression. Here, we review studies linking environment and HD in both humans and animal models. In HD patients, we find that: (i) an active lifestyle associates with both a delayed age at onset of HD and a decreased severity of symptoms, (ii) applying physical exercise and behavioral therapies in small cohorts of HD subjects indicate promising effects on the HD symptomatology, (iii) Mediterranean diet correlates with lower motor impairment, and treatments based on omega-3 fatty acids improve motor function , whereas (iv) increased cortisol levels associate with specific HD symptoms. In animal models, in line with the evidence in humans, physical exercise, environmental enrichment and different types of dietary intervention ameliorate or delay several HD phenotypes. In contrast, stress appears to be involved in the HD pathogenesis, and HD mice present increased stress sensitivity. Importantly, studies in animal models have uncovered several molecular factors mediating environmental effects on HD associated neuropathology. However, the influence of the environment on several key HD mechanisms as well as the underlying regulatory factors remain to be explored. Given the role of epigenetic factors and modifications in the interplay between environment and genes, the exploration of their role as mechanisms underlying the environmental action in HD is a promising avenue for both our fundamental understanding of the disease and as a potential for therapy.

Hypothalamic expression of huntingtin causes distinct metabolic changes in Huntington's disease mice.

OBJECTIVE: In Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating the role of metabolic changes in disease pathogenesis. Underlying mechanisms of metabolic changes in HD remain poorly understood, but recent studies suggest the involvement of hypothalamic dysfunction. The present study aimed to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models. METHODS: We used the R6/2 and BACHD mouse models that express different lengths of mutant HTT to develop lean- and obese phenotypes, respectively. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. The metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting-, and hindlimb clasping tests during early- and late-time points of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in the hypothalamus and adipose tissue. RESULTS: Hypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-gamma (PPARγ) in gonadal white adipose tissue was accompanied by distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression. CONCLUSIONS: Taken together, our findings provide further support for the role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.

Mendelian randomization study of coffee consumption and age at onset of Huntington's disease.

BACKGROUND & AIM: The association between habitual coffee or caffeine consumption and age at onset (AAO) of Huntington's disease (HD) is unclear. We employed Mendelian randomization to investigate the causal relationship between coffee consumption and AAO of HD. METHODS: The instrumental variable including 14 independent genetic variants associated with coffee consumption was selected from a genome-wide association study (GWAS) meta-analysis of 375,833 individuals of European ancestry. Genetic association estimates for AAO of HD were obtained from the Genetic Modifiers of Huntington's Disease Consortium GWAS meta-analysis including 9064 HD patients of European ancestry. The inverse variance weighted method was used to evaluate the causal estimate and a comprehensive set of analyses tested the robustness of our results. RESULTS: Genetically predicted higher coffee consumption was associated with an earlier AAO of HD (ß = -1.84 years, 95% confidence interval = -3.47 to -0.22, P = 0.026). Results were robust to potential pleiotropy and weak instrument bias. CONCLUSIONS: This genetic study suggests high coffee consumption is associated with an earlier AAO of HD. Coffee is widely consumed and thus our findings, if confirmed, offers a potential way to delay the onset of this debilitating autosomal dominant disease.

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy­linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine­responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD.

Hypothalamic pathology in Huntington disease.

Huntington's disease (HD), an autosomal dominant hereditary disorder associated with the accumulation of mutant huntingtin, is classically associated with cognitive decline and motor symptoms, notably chorea. However, growing evidence suggests that nonmotor symptoms are equally prevalent and debilitating. Some of these symptoms may be linked to hypothalamic pathology, demonstrated by findings in HD animal models and HD patients showing specific changes in hypothalamic neuropeptidergic populations and their associated functions. At least some of these alterations are likely due to local mutant huntingtin expression and toxicity, while others are likely caused by disturbed hypothalamic circuitry. Common problems include circadian rhythm disorders, including desynchronization of daily hormone excretion patterns, which could be targeted by novel therapeutic interventions, such as timed circadian interventions with light therapy or melatonin. However, translation of these findings from bench-to-bedside is hampered by differences in murine HD models and HD patients, including mutant huntingtin trinucleotide repeat length, which is highly heterogeneous across the various models. In this chapter, we summarize the current knowledge regarding hypothalamic alterations in HD patients and animal models, and the potential for these findings to be translated into clinical practice and management.

Therapeutic potential of ginsenoside Rg3 and Rf for Huntington's disease.

Ginseng is a popular herbal medicine and known to have protective and therapeutic effects in various diseases. Ginsenosides are active gradients representing the diverse pharmacological efficacy of ginseng. Huntington's disease (HD) is incurable genetic disorder associated with mutant huntingtin (mHtt) aggregation in the central nervous system. This study was conducted to investigate the effects of ginsenoside Rg3 and Rf on mHtt aggregation, cell viability, mitochondrial function, and apoptotic molecules on HD model. To investigate the effect of ginsenosides on HD, neural stem cells were isolated from the R6/2 mouse brain and used as a cellular model of HD. Nuclear aggregation of mHtt was measured by immunocytochemistry, and expressions of mitochondrial biogenesis and apoptotic molecules were investigated by western blot. As a result, the number of mHtt aggregates positive cells has decreased by ginsenoside Rg3 and Rf treatment in cellular model of HD. Mitochondrial biogenesis-related molecules such as PGC-1α and phosphorylated CREB were increased or showed increased tendency by ginsenoside Rg3 and Rf. Apoptotic molecules, p53, Bax, and cleaved caspase-3, were down-regulated by treatment of ginsenoside Rg3 and Rf. In addition, Lysotracker staining result showed that cellular lysosomal content was reduced by ginsenoside Rg3 and Rf. Given that ginsenoside Rg3 and Rf have the potential to reduce mHtt aggregation and cellular apoptosis, these ginsenosides can be possible therapeutic candidates for treating HD phenotypes.

Withaferin A Induces Heat Shock Response and Ameliorates Disease Progression in a Mouse Model of Huntington's Disease.

Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington's disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes.

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Alleviation of Huntington pathology in mice by oral administration of food additive glyceryl tribenzoate.

Huntington's disease (HD) is a neurodegenerative disorder characterized by accumulation of mutant huntingtin protein and significant loss of neurons in striatum and cortex. Along with motor difficulties, the HD patients also manifest anxiety and loss of cognition. Unfortunately, the clinically approved drugs only offer symptomatic relief and are not free from side effects. This study underlines the importance of glyceryl tribenzoate (GTB), an FDA-approved food flavoring ingredient, in alleviating HD pathology in transgenic N171-82Q mouse model. Oral administration of GTB significantly reduced mutant huntingtin level in striatum, motor cortex as well as hippocampus and increased the integrity of viable neurons. Furthermore, we found the presence of sodium benzoate (NaB), a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain of GTB-fed HD mice. Accordingly, NaB administration also markedly decreased huntingtin level in striatum and cortex. Glial activation is found to coincide with neuronal death in affected regions of HD brains. Interestingly, both GTB and NaB treatment suppressed activation of glial cells and inflammation in the brain. Finally, neuroprotective effect of GTB and NaB resulted in improved motor performance of HD mice. Collectively, these results suggest that GTB and NaB may be repurposed for HD.

Preclinical Nanomedicines for Polyglutamine-Based Neurodegenerative Diseases.

Polyglutamine (polyQ) diseases, such as Huntington's disease and several types of spinocerebellar ataxias, are dominantly inherited progressive neurodegenerative disorders and characterized by the presence of expanded CAG trinucleotide repeats in the respective disease locus of the patient genomes. Patients with polyQ diseases currently need to rely on symptom-relieving treatments because disease-modifying therapeutic interventions remain scarce. Many disease-modifying therapeutic agents are now under clinical testing for treating polyQ diseases, but their delivery to the brain is often too invasive (e.g., intracranial injection) or inefficient, owing to in vivo degradation and clearance by physiological barriers (e.g., oral and intravenous administration). Nanoparticles provide a feasible solution for improving drug delivery to the brain, as evidenced by an increasing number of preclinical studies that document the efficacy of nanomedicines for polyQ diseases over the past 5-6 years. In this review, we present the pathogenic mechanisms of polyQ diseases, the common animal models of polyQ diseases for evaluating the efficacy of nanomedicines, and the common administration routes for delivering nanoparticles to the brain. Next, we summarize the recent preclinical applications of nanomedicines for treating polyQ diseases and improving neurological conditions in vivo, placing emphasis on antisense oligonucleotides, small peptide inhibitors, and small molecules as the disease-modifying agents. We conclude with our perspectives of the burgeoning field of "nanomedicines for polyQ diseases", including the use of inorganic nanoparticles and potential drugs as next-generation nanomedicines, development of higher-order animal models of polyQ diseases, and importance of "brain-nano" interactions.

Cortical Network Dynamics Is Altered in Mouse Models of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric disturbances. Although evidence indicates that projections from motor cortical areas play a key role in the development of dysfunctional striatal activity and motor phenotype, little is known about the changes in cortical microcircuits and their role in the development of the HD phenotype. Here we used two-photon laser-scanning microscopy to evaluate network dynamics of motor cortical neurons in layers II/III in behaving transgenic R6/2 and knock-in Q175+/- mice. Symptomatic R6/2 mice displayed increased motion manifested by a significantly greater number of motion epochs, whereas symptomatic Q175 mice displayed decreased motion. In both models, calcium transients in symptomatic mice displayed reduced amplitude, suggesting decreased bursting activity. Changes in frequency were genotype- and time-dependent; for R6/2 mice, the frequency was reduced during both motion and nonmotion, whereas in symptomatic Q175 mice, the reduction only occurred during nonmotion. In presymptomatic Q175 mice, frequency was increased during both behavioral states. Interneuronal correlation coefficients were generally decreased in both models, suggesting disrupted interneuronal communication in HD cerebral cortex. These results indicate similar and contrasting effects of the HD mutation on cortical ensemble activity depending on mouse model and disease stage.

Bioenergetic deficits in Huntington's disease iPSC-derived neural cells and rescue with glycolytic metabolites.

Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington's disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.

Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

Selenium Nanoparticles as an Efficient Nanomedicine for the Therapy of Huntington's Disease.

Huntington's disease (HD) is an incurable disease with progressive loss of neural function, which is influenced by epigenetic, oxidative stress, metabolic, and nutritional factors. Targeting inhibition of huntingtin protein aggregation is a strategy for HD therapy, but the efficacy is unsatisfactory. Studies found that selenium (Se) levels in the brain are insufficient for HD disease individuals, while improvement in Se homeostasis in the brain may attenuate neuronal loss and dysfunction. In this study, we applied selenium nanoparticles (NPs) (Nano-Se) for the HD disease therapy by regulating HD-related neurodegeneration and cognitive decline based on transgenic HD models of Caenorhabditis elegans (C. elegans). At low dosages, Nano-Se NPs significantly reduced neuronal death, relieved behavioral dysfunction, and protected C. elegans from damages in stress conditions. The molecular mechanism further revealed that Nano-Se attenuated oxidative stress, inhibited the aggregation of huntingtin proteins, and downregulated the expression of histone deacetylase family members at mRNA levels. The results suggested that Nano-Se has great potential for Huntington's disease therapy. In conclusion, the mechanism about how Nano-Se NPs protect from damages in stress conditions and how they repair neural functions will benefit HD disease therapy. This study will also guide rational design of Nano-Se NPs or other selenium compounds to improve HD therapy in the future.

Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington's disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors.

Gintonin (GT), a ginseng-derived lysophosphatidic acid receptor ligand, regulates various cellular effects and represses inflammation. However, little is known about the potential value of GT regarding inflammation in the neurodegenerative diseases, such as Huntington's disease (HD). In this study, we investigated whether GT could ameliorate the neurological impairment and striatal toxicity in cellular or animal model of HD. Pre-, co-, and onset-treatment with GT (25, 50, or 100 mg/kg/day, p.o.) alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid (3-NPA). Pretreatment with GT also attenuated mitochondrial dysfunction i.e. succinate dehydrogenase and MitoSOX activities, apoptosis, microglial activation, and mRNA expression of inflammatory mediators i.e. IL-1ß, IL-6, TNF-α, COX-2, and iNOS in the striatum after 3-NPA-intoxication. Its action mechanism was associated with lysophosphatidic acid receptors (LPARs) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activations and the inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. These beneficial effects of GT were neutralized by pre-inhibiting LPARs with Ki16425 (a LPAR1/3 antagonist). Interestingly, GT reduced cell death and mutant huntingtin (HTT) aggregates in STHdh cells. It also mitigated neurological impairment in mice with adeno-associated viral (AAV) vector serotype DJ-mediated overexpression of N171-82Q-mutant HTT in the striatum. Taken together, our findings firstly suggested that GT has beneficial effects with a wide therapeutic time-window in 3-NPA-induced striatal toxicity by antioxidant and anti-inflammatory activities through LPA. In addition, GT exerts neuroprotective effects in STHdh cells and AAV vector-infected model of HD. Thus GT might be an innovative therapeutic candidate to treat HD-like syndromes.

ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.

Mitochondrial fragmentation and bioenergetic failure manifest in Huntington's disease (HD), a fatal neurodegenerative disease. The factors that couple mitochondrial fusion/fission with bioenergetics and their impacts on neurodegeneration however remain poorly understood. Our proteomic analysis identifies mitochondrial protein ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. Here we show that, in HD, ATAD3A dimerization due to deacetylation at K135 residue is required for Drp1-mediated mitochondrial fragmentation. Disturbance of ATAD3A steady state impairs mtDNA maintenance by disrupting TFAM/mtDNA binding. Blocking Drp1/ATAD3A interaction with a peptide, DA1, abolishes ATAD3A oligomerization, suppresses mitochondrial fragmentation and mtDNA lesion, and reduces bioenergetic deficits and cell death in HD mouse- and patient-derived cells. DA1 treatment reduces behavioral and neuropathological phenotypes in HD transgenic mice. Our findings demonstrate that ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance, suggesting that DA1 might be useful for developing HD therapeutics.