Motor Phenotype Research Articles

The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating the defective energy metabolism and components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the mechanisms by which the energy metabolism and the complement system are altered during the disease progression of ALS and how it can contribute to disease. Furthermore, it will also examine how complement activation can modify the energy metabolism in metabolic disorders, in order to highlight how the complement system and energy metabolism may be linked in ALS.

The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240) (1247)

The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240) (1247)

Epilepsy in LAMA2-related muscular dystrophy: An electro-clinico-radiological characterization.

To delineate the epileptic phenotype of LAMA2-related muscular dystrophy (MD) and correlate it with the neuroradiological and muscle biopsy findings, as well as the functional motor phenotype. Clinical, electrophysiological, neuroradiological, and histopathological data of 25 patients with diagnosis of LAMA2-related MD were analyzed. Epilepsy occurred in 36% of patients with LAMA2-related MD. Mean age at first seizure was 8years. The most common presenting seizure type was focal-onset seizures with or without impaired awareness. Visual aura and autonomic signs, including vomiting, were frequently reported. Despite a certain degree of variability, bilateral occipital or temporo-occipital epileptiform abnormalities were by far the most commonly observed. Refractory epilepsy was found in 75% of these patients. Epilepsy in LAMA2-related MD was significantly more prevalent in those patients in whom the cortical malformations were more extensive. In contrast, the occurrence of epilepsy was not found to be associated with the patients' motor ability, the size of their white matter abnormalities, or the amount of residual merosin expressed on muscle. The epileptic phenotype of LAMA2-related MD is characterized by focal seizures with prominent visual and autonomic features associated with EEG abnormalities that predominate in the posterior quadrants. A consistent correlation between epileptic phenotype and neuroimaging was identified, suggesting that the extension of the polymicrogyria may serve as a predictor of epilepsy occurrence.

Autosomal dominant GCH1 mutations causing spastic paraplegia at disease onset

BackgroundAutosomal dominant GCH1 mutations are known to cause dopa-responsive dystonia (DRD). In this case series, we confirm a variant phenotype, characterized by predominant spastic paraplegia at disease onset with development of dystonia and/or parkinsonism only decades later. MethodsClinical trajectories of four patients from three families with pathogenic variants in GCH1 are described, illustrated by videos of the motor phenotype before and during treatment with levodopa. An extensive literature review was performed on previous reports of spasticity in patients with autosomal dominant GCH1 mutations. ResultsAll patients presented during childhood or early adolescence with gait and leg spasticity. Three patients developed basal ganglia signs only in the fifth decade; the youngest patient has not yet developed dystonia, bradykinesia or hypokinesia. All patients responded to levodopa/carbidopa with improvement of gait and of dystonia, hypokinesia and/or rigidity. In all patients, spasticity decreased but did not disappear. Spasticity has been described previously in DRD, but in most cases co-existent basal ganglia signs were identified early in the disease course. ConclusionGCH1 mutations may cause a phenotype initially resembling hereditary spastic paraplegia (HSP) rather than DRD, with basal ganglia signs developing only after decades. In order not to miss this treatable condition, GCH1 should be included in HSP gene panels and its testing is pivotal in patients with spastic paraplegia, especially if there are concomitant basal ganglia signs and/or diurnal fluctuation.

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson's Disease.

The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson’s disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

Nurr1Cd11bcre conditional knockout mice display inflammatory injury to nigrostriatal dopaminergic neurons.

Nuclear receptor-related 1 protein (NURR1) is essential for the development and maintenance of midbrain dopaminergic (DAergic) neurons. NURR1 also protects DAergic neurons against neuroinflammation. However, it remains to be determined to what extent does NURR1 exerts its protective function through acting autonomously in the microglia. Using Cre/lox gene targeting system, we deleted Nurr1 in the microglia of Nurr1Cd11bcre conditional knockout (cKO) mice. The Nurr1Cd11bcre cKO mice displayed age-dependent motor abnormalities and increased microglial activation, but with no obvious DAergic neurodegeneration. To boost the inflammatory injury, we systemically administered endotoxin lipopolysaccharide (LPS) to Nurr1Cd11bcre mice. As expected, LPS treatment exacerbated the motor phenotypes and inflammatory reactions in Nurr1Cd11bcre cKO mice. More importantly, LPS administration caused DAergic neuron loss and α-synuclein aggregation, two pathological hallmarks of Parkinson's disease (PD). Therefore, our findings provide in vivo evidence supporting a critical protective role of NURR1 in the microglia against inflammation-induced degeneration of DAergic neurons in PD.

Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function.

Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function.

Dopamine Transporter, Age, and Motor Complications in Parkinson's Disease: A Clinical and Single-Photon Emission Computed Tomography Study.

Previous molecular imaging studies comparing dopamine function in vivo between early-onset PD and late-onset PD patients have shown contradictory results, presumably attributable to the aging-related decline in nigrostriatal function. (1) To investigate baseline dopamine transporter availability in early-onset PD (<55 years) and late-onset PD (>70 years) patients, z-scores values of putamen and caudate [123 I]-ioflupane uptake were calculated using the respective age-matched controls in order to correct for early presynaptic compensatory mechanisms and age-related dopamine neuron loss; (2) to examine the associations of such baseline single-photon emission computed tomography measures with the emergence of late-disease motor complications. In this retrospective study, 105 de novo PD patients who underwent [123 I]-ioflupane single-photon emission computed tomography at time of diagnosis were divided into three tertile groups according to age at disease onset (35 early-onset PD and 40 late-onset PD patients). Z-scores were compared between the two groups, and their predictive power for motor complications (during a mean follow-up of 7 years) was evaluated using Cox proportional hazard models. Despite a less-severe motor phenotype, early-onset PD patients exhibited more reduced [123 I]-ioflupane binding in the putamen and had a higher and earlier risk for developing motor complications than those with late-onset PD. Lower [123 I]-Ioflupane uptake in the putamen and caudate increased the risk of motor complications. Our findings indicate that a lower dopamine transporter binding in early-onset PD predicts the later development of motor complications, but it is not related to severity of motor symptoms, suggesting age-related differences in striatal compensatory mechanisms in PD. © 2020 International Parkinson and Movement Disorder Society.

Early-life trauma endophenotypes and brain circuit-gene expression relationships in functional neurological (conversion) disorder.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition whereby individuals present with sensorimotor symptoms incompatible with other neurological disorders. Early-life maltreatment (ELM) is a risk factor for developing FND, yet few studies have investigated brain network-trauma relationships in this population. In this neuroimaging–gene expression study, we used two graph theory approaches to elucidate ELM subtype effects on resting-state functional connectivity architecture in 30 patients with motor FND. 21 individuals with comparable depression, anxiety and ELM scores were used as psychiatric controls. Thereafter, we compared trauma endophenotypes in FND with regional-differences in transcriptional gene expression as measured by the Allen Human Brain Atlas (AHBA). In FND patients only, we found that early-life physical abuse severity, and to a lesser extent physical neglect, correlated with corticolimbic weighted-degree functional connectivity. Connectivity profiles influenced by physical abuse occurred in limbic (amygdalar-hippocampal), paralimbic (cingulo-insular and ventromedial prefrontal) and cognitive control (ventrolateral prefrontal) areas, as well as in sensorimotor and visual cortices. These findings held adjusting for individual-differences in depression/anxiety, PTSD and motor phenotypes. In FND, physical abuse also correlated with amygdala and insula coupling to motor cortices. In exploratory analyses, physical abuse correlated connectivity maps overlapped with the AHBA spatial expression of 3 gene-clusters: i) neuronal morphogenesis and synaptic transmission genes in limbic/paralimbic areas; ii) locomotory behavior and neuronal generation genes in left-lateralized structures; and iii) nervous system development and cell motility genes in right-lateralized structures. These circuit-specific architectural profiles related to individual differences in childhood physical abuse burden advance our understanding of the pathophysiology of FND.

Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro.

The gold standard for peripheral nerve regeneration uses a sensory autograft to bridge a motor/sensory defect site. For motor nerves to regenerate, Schwann cells (SC) myelinate the newly grown axon. Sensory SCs have a reduced ability to produce myelin, partially explaining low success rates of autografts. This issue is masked in pre-clinical research by the excessive use of the rat sciatic nerve defect model, utilizing a mixed nerve with motor and sensory SCs. Aim of this study was to utilize extracorporeal shockwave treatment as a novel tool to influence SC phenotype. SCs were isolated from motor, sensory and mixed rat nerves and in vitro differences between them were assessed concerning initial cell number, proliferation rate, neurite outgrowth as well as ability to express myelin. We verified the inferior capacity of sensory SCs to promote neurite outgrowth and express myelin-associated proteins. Motor Schwann cells demonstrated low proliferation rates, but strongly reacted to pro-myelination stimuli. It is noteworthy for pre-clinical research that sciatic SCs are a strongly mixed culture, not representing one or the other. Extracorporeal shockwave treatment (ESWT), induced in motor SCs an increased proliferation profile, while sensory SCs gained the ability to promote neurite outgrowth and express myelin-associated markers. We demonstrate a strong phenotype commitment of sciatic, motor, and sensory SCs in vitro, proposing the experimental use of SCs from pure cultures to better mimic clinical situations. Furthermore we provide arguments for using ESWT on autografts to improve the regenerative capacity of sensory SCs.

Deletion of the N-Terminus of Myosin Essential Light Chain (N-ELC) in the Background of HCM-A57G Mutation in Double Mutant Mice Rescues Hypercontractile Myosin Phenotype

Cardiac pathologic remodeling including fibrosis, diastolic dysfunction and increased Ca2+ sensitivity of force has been observed in mice expressing the A57G mutation in myosin ventricular ELC (MYL3 gene) with clinical phenotype of hypertrophic cardiomyopathy (HCM). Our previous investigation showed that the lack of the unique 43 amino acid-long N-terminus ELC (N-ELC) in >7-month-old Δ43 mice results in non-pathological cardiac hypertrophy. Papillary muscles (PM) from ∼8 mo-old Δ43 hearts were subjected to mantATP-chase assay and compared to those from age-matched WT-ELC and A57G mice. The data showed that Δ43 fibers favor the super-relaxed (SRX) state of myosin with increased population of slowly cycling heads compared to PM from age-matched WT-ELC mice. The opposite was true for A57G mice whose PM demonstrated a pathologic hypercontractile behavior with significantly inhibited SRX. We then tested the effect of N-ELC deletion in A57G mice on the SRX in offspring resulting from breeding Δ43 with A57G mice (Δ43xA57G) and expressing 0-22% of Δ43 and 0-84% of A57G. Single nucleotide turnover assays on PM from all Δ43xA57G animals showed stabilization of the SRX state that was reminiscent of Δ43 alone, and different from all other groups of mice. Interestingly, echocardiographic evaluation of ∼8-month-old Δ43xA57G mice revealed a decrease in cardiac hypertrophy (decrease in LV mass) compared to A57G and Δ43 animals. Myocardial performance index was also improved in Δ43xA57G crosses compared to HCM-A57G mice, and not different compared to WT or Δ43 mice. Our studies suggest that the deletion of N-ELC in the background of HCM-ELC mutation may be beneficial in reversing some of the pathological myosin motor phenotypes associated with HCM. Supported by NIH R01HL123255 and R56HL146133 (DSC).

Early-Motor Phenotype Relates to Neuropsychiatric and Cognitive Disorders in Huntington's Disease.

To determine the relationships between the motor phenotype and the presence of specific neuropsychiatric and neuropsychological disorders in patients with early motor-manifest Huntington's disease (HD). From the Enroll-HD study, 3,505 individuals with HD who had ≤5 years of motor symptoms were classified based on the predefined parkinsonism/chorea index into chorea-dominant (n = 1125), parkinsonism-dominant (n = 867), and mixed-motor phenotype (n = 1513) groups. An analysis was performed on the results of the short Problem Behaviors Assessment. This test assesses patients for neuropsychiatric disorders such as depression, irritability/aggression, apathy, obsessive-compulsive behaviors, and psychosis as well as cognitive disorders by using neuropsychological tests such as the Stroop Interference test, Trail Making Test Part A and B, letter fluency, Symbol Digit Modality test, and animal fluency test. In these early motor-manifest HD individuals, motor phenotype was associated with neuropsychiatric and cognitive changes. Independent of the age of motor onset, motor duration and severity, CAG repeat expansion, and medication use, the parkinsonism-dominant group had more severe neuropsychiatric disorders (depression, apathy, obsessive-compulsive behaviors, and psychosis) and poorer performance on all cognitive tests than those patients in the mixed-motor phenotype and chorea-dominant groups. The patients in the chorea-dominant group had less apathy and depression than those in the mixed-motor phenotype group. In the early stage of motor-manifest HD, parkinsonism-dominant patients appear to have more severe neuropsychiatric disturbances and more cognitive impairments than those HD patients with chorea-dominant and mixed-motor phenotypes. Future studies should explore the brain mechanisms of these disorders and the possible treatments. © 2020 International Parkinson and Movement Disorder Society.

Picalm reduction exacerbates tau pathology in a murine tauopathy model.

Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/-by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/- mice developed markedly more severe motor deficits than Tg30 by the age of 9months. Tg30xPicalm+/- had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

Self-perceptions of speech, voice, and swallowing in motor phenotypes of Parkinson's disease

IntroductionThe ability of people with Parkinson's Disease (PWPD) to perceive and identify impairments related to communication and swallowing is often impaired. This impairment prolongs the time to diagnosis of dysphonia and dysphagia, and can delay implementation of speech or swallowing therapy. We have limited knowledge of how different motor phenotypes of PD impact speech, voice and swallowing, nor how PWPD perceive these impacts. The purpose of this study was to identify how perceptions of speech and voice impairments predict dysphagia in PD, and how those perceptions differ between motor phenotypes. Methods38 PWPD completed clinical surveys including V-RQOL, DHI, and a speech, voice, and swallow symptom questionnaire. Participants were categorized as either tremor dominant (TD) or non-tremor dominant (NTD) phenotypes. Multiple regression and MANOVA were utilized to identify predictors of dysphagia perceptions, and for differentiating between motor phenotype based on perceptual severity. ResultsPerceptions of speech and voice impairment predicted perceptions of swallow impairment regardless of phenotype (p < .05, CI = 0.08–0.77). NTD participants reported significantly more communication and swallowing impairments than TD (p < .05) and perceived communication impairment severity was the strongest predictor of group classification (OR = 0.50). The survey battery displayed a robust discriminatory ability between phenotype (AUC = 0.87, CI = 0.76–0.98). ConclusionThe use of a noninvasive and cost-efficient survey battery may be useful in predicting patient perceived swallow impairment in PWPD. Speech, voice, and swallow impairments based on survey responses were found to differ between motor phenotypes.

Animal models for preclinical Parkinson's research: An update and critical appraisal.

Animal models of Parkinson's disease (PD) are essential to investigate pathogenic pathways at the whole-organism level. Moreover, they are necessary for a preclinical investigation of potential new therapies. Different pathological features of PD can be induced in a variety of invertebrate and vertebrate species using toxins, drugs, or genetic perturbations. Each model has a particular utility and range of applicability. Invertebrate PD models are particularly useful for high throughput-screening applications, whereas mammalian models are needed to explore complex motor and non-motor features of the human disease. Here, we provide a comprehensive review and critical appraisal of the most commonly used mammalian models of PD, which are produced in rats and mice. A substantial loss of nigrostriatal dopamine neurons is necessary for the animal to exhibit a hypokinetic motor phenotype responsive to dopaminergic agents, thus resembling clinical PD. This level of dopaminergic neurodegeneration can be induced using specific neurotoxins, environmental toxicants, or proteasome inhibitors. Alternatively, nigrostriatal dopamine degeneration can be induced via overexpression of α-synuclein using viral vectors or transgenic techniques. In addition, protein aggregation pathology can be triggered by inoculating preformed fibrils of α-synuclein in the substantia nigra or the striatum. Thanks to the conceptual and technical progress made in the past few years a vast repertoire of well-characterized animal models are currently available to address different aspects of PD in the laboratory.

A galactose-1-phosphate uridylyltransferase-null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue-specific and longitudinal differences in galactose metabolism.

Classic galactosemia (CG) is a potentially lethal inborn error of metabolism, if untreated, that results from profound deficiency of galactose‐1‐phosphate uridylyltransferase (GALT), the middle enzyme of the Leloir pathway of galactose metabolism. While newborn screening and rapid dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms of CG, by mid‐childhood, most treated patients experience significant complications. The mechanisms underlying these long‐term deficits remain unclear. Here we introduce a new GALT‐null rat model of CG and demonstrate that these rats display cataracts, cognitive, motor, and growth phenotypes reminiscent of patients outcomes. We further apply the GALT‐null rats to test how well blood biomarkers, typically followed in patients, reflect metabolic perturbations in other, more relevant tissues. Our results document that the relative levels of galactose metabolites seen in GALT deficiency differ widely by tissue and age, and that red blood cell Gal‐1P, the marker most commonly followed in patients, shows no significant association with Gal‐1P in other tissues. The work reported here establishes our outbred GALT‐null rats as an effective model for at least four complications characteristic of CG, and sets the stage for future studies addressing mechanism and testing the efficacy of novel candidate interventions.

Behavioral defects associated with amygdala and cortical dysfunction in mice with seeded α-synuclein inclusions

Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons, but unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning, tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.

GASTROINTESTINAL DYSFUNCTIONS AND PERIPHERAL INFLAMMATORY CYTOKINES IN PARKINSON’S DISEASES

Parkinson’s disease (PD) is a neurodegenerative disease characterized by α-synucleinopathy, which involves all districts of the brain-gut axis, including the central, autonomic and enteric nervous systems. Previous findings suggest that the intestinal microbiome is altered in PD and is related to motor phenotype. However how dysbiosis arises and whether this feature contributes to PD pathogenesis remains unknown. The aim was to evaluate gut microbiome and the serum cytokine profile in PD. We quantified serum interleukin (IL) levels (IL-1β, IL-6, IL-10, TNF-α, IFN-γ) in 55 PD patients. Study of the fecal samples was performed by real time PCR method and bacteriologically. Discovered the relationship between the intensity of dysbiosis and the level of proinflammatory cytokine IFN-γ, IL-6.We show that disturbances in plasma cytokine level could be more profound in PD patients with altered composition of intestinal microbiota, which may explain the mechanism of influence of microbiota composition on the PD manifestations.

Rodent genetic models of neurodevelopmental disorders and epilepsy.

Neurodevelopmental disorders (NDDs) are characterised by cognitive, social and motor deficits and are highly comorbid with intractable epilepsies. Through advances in genetic sequencing technologies a vast number of genes have been implicated in NDDs. State-of-the-art gene-editing techniques have led to the generation of hundreds of mouse models of NDDs. As an example, rodent models of Rett and Dravet syndromes as well as the syndromes caused by mutations in CDKL5 and Syngap1 display cognitive deficits in conjunction with seizure phenotypes. These models allow researchers to understand the underlying mechanisms as well as develop novel treatment strategies that can potentially be translated to the clinic. Furthermore, it may be possible to gain insights into the contribution of epilepsy to the progression of cognitive, social and motor phenotypes in NDDs.

Longitudinal study revealing motor, cognitive and behavioral decline in a transgenic minipig model of Huntington's disease.

ABSTRACTHuntington's disease (HD) is an inherited devastating neurodegenerative disease with no known cure to date. Several therapeutic treatments for HD are in development, but their safety, tolerability and efficacy need to be tested before translation to bedside. The monogenetic nature of this disorder has enabled the generation of transgenic animal models carrying a mutant huntingtin (mHTT) gene causing HD. A large animal model reflecting disease progression in humans would be beneficial for testing the potential therapeutic approaches. Progression of the motor, cognitive and behavioral phenotype was monitored in transgenic Huntington's disease minipigs (TgHD) expressing the N-terminal part of human mHTT. New tests were established to investigate physical activity by telemetry, and to explore the stress-induced behavioral and cognitive changes in minipigs. The longitudinal study revealed significant differences between 6- to 8-year-old TgHD animals and their wild-type (WT) controls in a majority of the tests. The telemetric study showed increased physical activity of 4.6- to 6.5-year-old TgHD boars compared to their WT counterparts during the lunch period as well as in the afternoon. Our phenotypic study indicates progression in adult TgHD minipigs and therefore this model could be suitable for longstanding preclinical studies of HD.This article has an associated First Person interview with the first author of the paper.