Improved Mathematical Models of Parkinson's Disease with Hopf Bifurcation and Huntington's Disease with Chaos.

Using delay differential equations to study mathematical models of Parkinson's disease and Huntington's disease is important to show how important it is for synchronization between basal ganglia loops to work together. We used the delay circuit RLC (resistor, inductor, capacitor) model to show how the direct pathway and the indirect pathway in the basal ganglia excite and inhibit the motor cortex, respectively. A term has been added to the mathematical model without time delay in the case of the hyperdirect pathway. It is proposed to add a non-linear term to adjust the synchronization. We studied Hopf bifurcation conditions for the proposed models. The desynchronization of response times between the direct pathway and the indirect pathway leads to different symptoms of Parkinson's disease. Tremor appears when the response time in the indirect pathway increases at rest. The simulation confirmed that tremor occurs and the motor cortex is in an inhibited state. The direct pathway can increase the time delay in the dopaminergic pathway, which significantly increases the activity of the motor cortex. The hyperdirect pathway regulates the activity of the motor cortex. The simulation showed bradykinesia occurs when we switch from one movement to another that is less exciting for the motor cortex. A decrease of GABA in the striatum or delayed excitation of the substantia nigra from the subthalamus may be a major cause of Parkinson's disease. An increase in the response time delay in one of the pathways results in the chaotic movement characteristic of Huntington's disease.

Neurodegenerative disorders, metabolic icebergs, and mitohormesis.

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Two novel DnaJ chaperone proteins CG5001 and P58IPK regulate the pathogenicity of Huntington's disease related aggregates.

Huntington's disease (HD) is a rare neurodegenerative disease caused due to aggregation of Huntingtin (HTT) protein. This study involves the cloning of 40 DnaJ chaperones from Drosophila, and overexpressing them in yeasts and fly models of HD. Accordingly, DnaJ chaperones were catalogued as enhancers or suppressors based on their growth phenotypes and aggregation properties. 2 of the chaperones that came up as targets were CG5001 and P58IPK. Protein aggregation and slow growth phenotype was rescued in yeasts, S2 cells, and Drosophila transgenic lines of HTT103Q with these overexpressed chaperones. Since DnaJ chaperones have protein sequence similarity across species, they can be used as possible tools to combat the effects of neurodegenerative diseases.

RNA Editing by ADAR Adenosine Deaminases in the Cell Models of CAG Repeat Expansion Diseases: Significant Effect of Differentiation from Stem Cells into Brain Organoids in the Absence of Substantial Influence of CAG Repeats on the Level of Editing.

Expansion of CAG repeats in certain genes is a known cause of several neurodegenerative diseases, but exact mechanism behind this is not yet fully understood. It is believed that the double-stranded RNA regions formed by CAG repeats could be harmful to the cell. This study aimed to test the hypothesis that these RNA regions might potentially interfere with ADAR RNA editing enzymes, leading to the reduced A-to-I editing of RNA and activation of the interferon response. We studied induced pluripotent stem cells (iPSCs) derived from the patients with Huntington's disease or ataxia type 17, as well as midbrain organoids developed from these cells. A targeted panel for next-generation sequencing was used to assess editing in the specific RNA regions. Differentiation of iPSCs into brain organoids led to increase in the ADAR2 gene expression and decrease in the expression of protein inhibitors of RNA editing. As a result, there was increase in the editing of specific ADAR2 substrates, which allowed identification of differential substrates of ADAR isoforms. However, comparison of the pathology and control groups did not show differences in the editing levels among the iPSCs. Additionally, brain organoids with 42-46 CAG repeats did not exhibit global changes. On the other hand, brain organoids with the highest number of CAG repeats in the huntingtin gene (76) showed significant decrease in the level of RNA editing of specific transcripts, potentially involving ADAR1. Notably, editing of the long non-coding RNA PWAR5 was nearly absent in this sample. It could be stated in conclusion that in most cultures with repeat expansion, the hypothesized effect on RNA editing was not confirmed.

Dermal Fibroblast Cell Line from a Patient with the Huntington's Disease as a Promising Model for Studying Disease Pathogenesis: Production and Characterization.

Huntington's disease (HD) is an incurable hereditary disease caused by expansion of the CAG repeats in the HTT gene encoding the mutant huntingtin protein (mHTT). Despite numerous studies in cellular and animal models, the mechanisms underlying the biological role of mHTT and its toxicity to striatal neurons have not yet been established and no effective therapy for HD patients has been developed so far. We produced and characterized a new line of dermal fibroblasts (HDDF, Huntington's disease dermal fibroblasts) from a patient with a confirmed HD diagnosis. We also studied the growth characteristics of HDDF cells, stained them for canonical markers, karyotyped these cells, and investigated their phenotype. HDDF cells was successfully reprogrammed into induced striatal neurons via transdifferentiation. The new fibroblast line can be used as a cell model to study the biological role of mHTT and manifestations of HD pathogenesis in both fibroblasts and induced neuronal cells obtained from them by reprogramming techniques.

The Imidazoline Receptors as a new therapeutic target in Huntington's disease: A Preclinical Overview.

An autosomal dominant neurodegenerative disease called Huntington's disease (HD) is characterized by motor dysfunction, cognitive decline, and a variety of psychiatric symptoms due to the expansion of polyglutamine in the Huntington gene. The disease primarily affects the striatal neurons within the basal ganglia, leading to significant neuronal loss and associated symptoms such as chorea and dystonia. Current therapeutic approaches focus on symptom management without altering the disease's progression, highlighting a pressing need for novel treatment strategies. Recent studies have identified imidazoline receptors (IRs) as promising targets for neuroprotective and disease-modifying interventions in HD. IRs, particularly the I1 and I2 subtypes, are involved in critical physiological processes such as neurotransmission, neuronal excitability, and cell survival. Activation of these receptors has been shown to modulate neurotransmitter release and provide neuroprotective effects in preclinical models of neurodegeneration. This paper discusses the potential of IR-targeted therapies to not only alleviate multiple symptoms of HD but also possibly slow the progression of the disease. We emphasize the necessity for ongoing research to further elucidate the roles of IRs in HD and develop selective ligands that could lead to effective and safe treatments, thereby significantly improving patient outcomes and quality of life.

Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment.

Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the electron transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen and reactive nitrogen species (ROS and RNS). The associated progressive accumulation of molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger and indirect antioxidant, is synthesized in the mitochondrial matrix of neurons. Melatonin reduces electron leakage from the ETC and elevates ATP production; it also detoxifies ROS/RNS and via the SIRT3/FOXO pathway it upregulates activities of superoxide dismutase 2 and glutathione peroxidase. Melatonin also influences glucose processing by neurons. In neurogenerative diseases, neurons often adopt Warburg-type metabolism which excludes pyruvate from the mitochondria causing reduced intramitochondrial acetyl coenzyme A production. Acetyl coenzyme A supports the citric acid cycle and OXPHOS. Additionally, acetyl coenzyme A is a required co-substrate for arylalkylamine-N-acetyl transferase, which rate limits melatonin synthesis; therefore, melatonin production is diminished in cells that experience Warburg-type metabolism making mitochondria more vulnerable to oxidative stress. Moreover, endogenously produced melatonin diminishes during aging, further increasing oxidative damage to mitochondrial components. More normal mitochondrial physiology is preserved in aging neurons with melatonin supplementation.

Luteolin as potential treatment for Huntington's disease: Insights from a transgenic mouse model.

AIMS: The study aimed to evaluate the potential benefits of luteolin treatment in Huntington's disease (HD), an inherited progressive neurodegenerative disorder. METHODS: HD N171-82Q transgenic and WT mice received luteolin or vehicle for treatment at 6 weeks of age. The mice's body weight changes and survival rates were monitored throughout the study, and a series of motor functional tests were conducted. Serum level of the marker NfL was also determined. Immunohistochemical staining and western blotting were utilized to assess the expression of huntingtin aggregates. RESULTS: Luteolin treatment enhanced survival and prevented weight loss in HD mice compared to the vehicle-treated HD group. Furthermore, the luteolin-treated HD mice exhibited enhanced motor coordination and balance and significantly reduced motor dysfunction. Also, luteolin decreased serum NfL levels in HD mice. Notably, the accumulation of huntingtin aggregates was significantly reduced in the brain's cortex, hippocampus, and striatum of luteolin-treated HD mice compared to the vehicle-treated HD group. CONCLUSION: Luteolin holds promise as a therapeutic agent for improving survival outcomes, managing motor dysfunction, and reducing huntingtin aggregates in HD. The findings are of significance as currently, there are no approved therapeutic interventions that reverse HD pathology or slow down its progression.

The meaning of apathy in Huntington's disease: A qualitative study of caregiver perspectives.

Although one of the most prevalent and impactful features of Huntington's disease (HD), little is known about the impact of apathy on HD caregivers, although there is evidence it affects perceptions of distress and burden. Given the importance of the caregivers, we aimed to explore the lived experience of people supporting someone with HD and associated apathy. Semi-structured interviews were conducted with 11 caregivers and analysed using reflective thematic analysis, informed by a phenomenological framework. Five overarching themes were produced: (1) What even is apathy? (2) It makes my life harder: the practical impact of apathy, (3) They haven't forgotten me, but they have forgotten that they ever loved me, (4) I'm grieving for someone who hasn't died yet, and (5) I need a safe space to say what I really feel without fear of judgement. Inter-woven between these themes were complex narratives about the unspoken nature of HD, the invisibility of caregivers who felt trapped and unheard, and the one-sided nature of loving someone with the disease. Findings are discussed in relation to theoretical frameworks of anticipatory grief and ambiguous loss, and situated within the wider literature on caregiving for people with a neurodegenerative condition.

Virtual reality tolerability, sense of presence and usability in Huntington disease: a pilot study.

INTRODUCTION: Several studies demonstrated the utility of immersive virtual reality (VR) as a complementary approach to conventional therapy for improving motor, psychological and cognitive impairment in some pathological conditions. Our pilot study aims to evaluate for the first time: 1) sense of presence, tolerability and usability of VR immersive experience in patients with early stages of Huntington disease (eHDp) compared to healthy controls (HC); 2) correlation between the use of technology/cybersickness and the variables of presence/usability; 3) correlation between clinical characteristics (genetic, motor, functional and cognitive) and VR's variables. METHOD: We recruited 10 eHDp and 10 age, gender and education matched HC. Participants completed questionnaires about sense of presence, usability, tolerability and technology use profile. Subjects were exposed to different VR scenarios from a first-person perspective through a standalone VR headset. RESULTS: Our results showed no significant statistical difference between eHDp and HC for the sense of presence (p=0.910), usability (p=0.744) and tolerability (p=0.730) during the VR experience. Familiarity with the use of technology was also comparable between groups (p=0.676). Regarding correlations in eHDp group, our results showed no correlations between use of technology/tolerability and the sense of presence/usability. Moreover, clinical characteristics of eHDp (genetic, motor, functional and cognitive scores) did not influence the sense of presence, tolerability and usability. CONCLUSION: Our research presents preliminary evidence for the applicability of VR in eHDp. These results open up the possibility to explore future applications of this methodology in rehabilitation (i.e., cognitive training, physiotherapy), diagnosis and psychological support in Huntington disease patients.

Interaction between resveratrol and SIRT1: role in neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, pose significant health challenges and economic burdens worldwide. Recent studies have emphasized the potential therapeutic value of activating silent information regulator-1 (SIRT1) in treating these conditions. Resveratrol, a compound known for its ability to potently activate SIRT1, has demonstrated promising neuroprotective effects by targeting the underlying mechanisms of neurodegeneration. In this review, we delve into the crucial role of resveratrol-mediated SIRT1 upregulation in improving neurodegenerative diseases. The role of the activation of SIRT1 by resveratrol was reviewed. Moreover, network pharmacology was used to elucidate the possible mechanisms of resveratrol in these diseases. Activation of SIRT1 by resveratrol had positive effects on neuronal function and survival and alleviated the hallmark features of these diseases, such as protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In terms of network pharmacology, the signaling pathways by which resveratrol protects against different neurodegenerative diseases were slightly different. Although the precise mechanisms underlying the neuroprotective effects of resveratrol and SIRT1 activation remain under investigation, these findings offer valuable insights into potential therapeutic strategies for neurodegenerative diseases.

The Frequency and Clinical Impact of Synonymous HTT Loss-of-Interruption and Duplication-of-interruption Variants in a Diverse HD Cohort.

PURPOSE: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption (DOI) modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD). METHODS: We screened symptomatic HD participants from the UBC HD Biobank and five research sites for sequence variants. Following variant identification, we examined the clinical impact and frequency in the reduced penetrance range. RESULTS: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of TMS by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of two symptomatic HD participants with diagnostic repeats below the pathogenetic range. CONCLUSION: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cut-off ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.

Stress-Related Roles of Exosomes and Exosomal miRNAs in Common Neuropsychiatric Disorders.

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review.

Beneficial effects of miR-132/212 deficiency in the zQ175 mouse model of Huntington's disease.

Huntington's disease (HD) is a rare genetic neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. One hypothesis suggests that the mutant HTT gene contributes to HD neuropathology through transcriptional dysregulation involving microRNAs (miRNAs). In particular, the miR-132/212 cluster is strongly diminished in the HD brain. This study explores the effects of miR-132/212 deficiency specifically in adult HD zQ175 mice. The absence of miR-132/212 did not impact body weight, body temperature, or survival rates. Surprisingly, miR-132/212 loss seemed to alleviate, in part, the effects on endogenous Htt expression, HTT inclusions, and neuronal integrity in HD zQ175 mice. Additionally, miR-132/212 depletion led to age-dependent improvements in certain motor functions. Transcriptomic analysis revealed alterations in HD-related networks in WT- and HD zQ175-miR-132/212-deficient mice, including significant overlap in BDNF and Creb1 signaling pathways. Interestingly, however, a higher number of miR-132/212 gene targets was observed in HD zQ175 mice lacking the miR-132/212 cluster, especially in the striatum. These findings suggest a nuanced interplay between miR-132/212 expression and HD pathogenesis, providing potential insights into therapeutic interventions. Further investigation is needed to fully understand the underlying mechanisms and therapeutic potential of modulating miR-132/212 expression during HD progression.

Person-centred integrated care for people living with Parkinson's, Huntington's and Multiple Sclerosis: A systematic review.

INTRODUCTION: People living with long-term neurological conditions (LTNCs) have complex needs that demand intensive care coordination between sectors. This review aimed to establish if integrated care improves outcomes for people, and what characterises successful interventions. METHODS: A systematic review of the literature was undertaken evaluating multisectoral integrated care interventions in people living with Parkinson's disease (PD), Multiple Sclerosis (MS) and Huntington's disease (HD). Strength of evidence was rated for the different outcomes. RESULTS: A total of 15 articles were included, reporting on 2095 patients and caregivers, finding that integrated care can improve people's access to resources and reduce patients' depression. UK studies indicated improvements in patients' quality of life, although the international literature was inconclusive. Few programmes considered caregivers' outcomes, reporting no difference or even worsening in depression, burden and quality of life. Overall, the evidence showed a mismatch between people's needs and outcomes measured, with significant outcomes (e.g., self-management, continuity of care, care experience) lacking. Successful programmes were characterised by expert knowledge, multisectoral care coordination, care continuity and a person-centred approach. CONCLUSIONS: The impact of integrated care programmes on people living with LTNCs is limited and inconclusive. For a more person-centred approach, future studies need to assess integrated care from a service-user perspective. PATIENT AND PUBLIC CONTRIBUTION: Thirty people living with LTNCs were involved in this review, through defining research questions, validating the importance of the project, and increasing the researchers' understanding on what matters to service users. A patient and public involvement subgroup of representatives with lived experience on PD, MS and HD identified the need for more person-centred integrated care, with specific concerns over care fragmentation, care duplication and care continuity. This was key to data analysis and formulating the characteristics of successful and unsuccessful integrated care programmes from the perspective of service users. The discrepancy between service users' needs and the outcomes assessed in the literature point to user-driven research as the solution to address what matters to patients and caregivers.

An automatic measure for speech intelligibility in dysarthrias-validation across multiple languages and neurological disorders.

Introduction: Dysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework. Methods: The study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants' speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed. Results: Verification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability. Discussion: The ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.

Optical coherence tomography measurements in Huntington's disease: a systematic review and meta-analysis.

BACKGROUND: A connection has been established between ocular structural changes and various neurodegenerative diseases. Several studies utilizing optical coherence tomography (OCT) have detected signs of ocular structural alterations among individuals with Huntington's disease (HD). The inconsistent results reported in the literature regarding alterations in the retina and choroid encouraged us to conduct this systematic review and meta-analysis to accumulate the findings. METHODS: A systematic search was carried out in three electronic databases (PubMed, Embase, Scopus) to find studies reporting OCT measurements in HD cases compared with healthy controls (HC). A fixed-effects or random-effects meta-analysis was conducted according to the detected heterogeneity level. Furthermore, subgroup and sensitivity analyses, meta-regression, and quality assessment were performed. RESULTS: Eleven studies were included in the systematic review and 9 studies with a total population of 452 participants (241 cases, and 211 HC) underwent meta-analysis. Results of the analysis denoted that subfoveal choroid had a significantly reduced thickness in HD eyes compared to HC (p < 0.0001). Moreover, our analysis indicated that HD cases had a significantly thinner average (p = 0.0130) and temporal peripapillary retinal nerve fiber layer (pRNFL) (p = 0.0012) than HC. However, subjects with pre-HD had insignificant differences in average (p = 0.44) and temporal pRNFL thickness (p = 0.33) with the HC group. CONCLUSION: Results of the current systematic review and meta-analysis revealed the significant thinning of average and temporal pRNFL and subfoveal choroid in HD compared to HC. However, OCT currently might be considered insensitive to be applied in the pre-HD population at least until further longitudinal investigations considering variables such as the duration between OCT measurement and disease onset validating OCT as a routine diagnostic tool in HD clinics.

Emerging pharmacological approaches for Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by cognitive, motor, and psychiatric symptoms. Despite significant advances in understanding the underlying molecular mechanisms of HD, there is currently no cure or disease-modifying treatment available. Emerging pharmacological approaches offer promising strategies to alleviate symptoms and slow down disease progression. This comprehensive review aims to provide a critical appraisal of the latest developments in pharmacological interventions for HD. The review begins by discussing the pathogenesis of HD, focusing on the role of mutant huntingtin protein, mitochondrial dysfunction, excitotoxicity, and neuro-inflammation. It then explores emerging therapeutic targets, including the modulation of protein homeostasis, mitochondrial function, neuro-inflammation, and neurotransmitter systems. Pharmacological agents targeting these pathways are discussed, including small molecules, gene-based therapies, and neuroprotective agents. In recent years, several clinical trials have been conducted to evaluate the safety and efficiency of novel compounds for HD. This review presents an update on the outcomes of these trials, highlighting promising results and challenges encountered. Additionally, it discusses the potential of repurposing existing drugs approved for other indications as a cost-effective approach for HD treatment. The review concludes by summarizing the current state of pharmacological approaches for HD and outlining future directions in drug development. The integration of multiple therapeutic strategies, personalized medicine approaches, and combination therapies are highlighted as potential avenues to maximize treatment effectiveness.

Scheduled feeding improves sleep in a mouse model of Huntington's disease.

Sleep disturbances are common features of neurodegenerative disorders including Huntington's disease (HD). Sleep and circadian disruptions are recapitulated in animal models, providing the opportunity to evaluate the effectiveness of circadian interventions as countermeasures for neurodegenerative disease. For instance, time restricted feeding (TRF) successfully improved activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) adult mice, under TRF and ad lib feeding (ALF). Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding in a sex-dependent manner. The treatment did impact the power spectral curves during the day in male but not female mice regardless of the genotype. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.

Pathogenic TDP-43 accelerates the generation of toxic exon1 HTT in Huntington's disease knock-in mice.

Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length-dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre-mRNA, promotes the transport of exon1-intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.