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1.
Nat Commun ; 12(1): 364, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441541

RESUMO

Temporal dynamics and mechanisms underlying epigenetic changes in Huntington's disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.


Assuntos
Envelhecimento , Montagem e Desmontagem da Cromatina/genética , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Doença de Huntington/genética , Doenças Neurodegenerativas/genética , Animais , Comportamento Animal/fisiologia , Cromatina/genética , Corpo Estriado/citologia , Corpo Estriado/fisiopatologia , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Proteína Huntingtina/genética , Doença de Huntington/diagnóstico , Doença de Huntington/fisiopatologia , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
2.
Gene ; 765: 145133, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32898606

RESUMO

Huntington's disease (HD), caused by expansion of CAG repeats in the 1st exon of the HTT gene, is a disorder inherited in an autosomal dominant manner. HD symptoms include chorea, behavioral disturbances and cognitive decline. Although it is described as a neurodegenerative disease, due to expression of HTT in all types of cells, peripheral symptoms also occur. R6/1 and R6/2 mouse lines, which demonstrate many different phenotypical disturbances, are among the most commonly used HD animal models. Nevertheless, in this report, we underlined, for the first time, a previously undescribed R6/1 and R6/2 feature, hair dysmorphology. We observed changes in the general view of pelage, as well as specific changes in the shape of hair, assessed under electron microscope (deep cavity and hilly hair surface or concave and convex areas on the long hair axis with an appearance of the hair as flat). Hair diameter was significantly increased in both HD mouse models relative to control animals. Moreover, loosened contact between the scales and loosened scale texture were observed in R6/1 and R6/2. Thus, this study highlighted that the hair morphology might be a useful, noninvasive and simple marker of a widely used HD mouse models, R6/1 and R6/2 lines, particularly in testing effects of potential therapeutics or disease progression.


Assuntos
Pelo Animal/química , Pelo Animal/metabolismo , Doença de Huntington/diagnóstico , Animais , Modelos Animais de Doenças , Cabelo/química , Cabelo/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Doenças Neurodegenerativas/metabolismo , Fenótipo
3.
PLoS One ; 15(12): e0243052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370315

RESUMO

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by severe disruption of cognitive and motor functions, including changes in posture and gait. A number of HD mouse models have been engineered that display behavioral and neuropathological features of the disease, but gait alterations in these models are poorly characterized. Sensitive high-throughput tests of fine motor function and gait in mice might be informative in evaluating disease-modifying interventions. Here, we describe a hypothesis-free workflow that determines progressively changing locomotor patterns across 79 parameters in the R6/2 and Q175 mouse models of HD. R6/2 mice (120 CAG repeats) showed motor disturbances as early as at 4 weeks of age. Similar disturbances were observed in homozygous and heterozygous Q175 KI mice at 3 and 6 months of age, respectively. Interestingly, only the R6/2 mice developed forelimb ataxia. The principal components of the behavioral phenotypes produced two phenotypic scores of progressive postural instability based on kinematic parameters and trajectory waveform data, which were shared by both HD models. This approach adds to the available HD mouse model research toolbox and has a potential to facilitate the development of therapeutics for HD and other debilitating movement disorders with high unmet medical need.


Assuntos
Análise da Marcha/métodos , Proteína Huntingtina/genética , Doença de Huntington/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Feminino , Doença de Huntington/genética , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora , Mutação , Postura
4.
Life Sci ; 257: 118076, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32659371

RESUMO

AIMS: Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances. MATERIAL AND METHODS: Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1ß, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted. KEY FINDINGS: 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters. SIGNIFICANCE: Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glicólise/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar
5.
PLoS One ; 15(6): e0234394, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574176

RESUMO

In the BACHD mouse model of Huntington's disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered -but differentially so- in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31 -but not Q97- MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model.


Assuntos
Proteína Huntingtina/genética , Doença de Huntington/genética , Potenciais de Ação , Animais , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Dendritos/patologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores , Feminino , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/fisiologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Coxeadura Animal/genética , Coxeadura Animal/fisiopatologia , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Domínios Proteicos , Reflexo Anormal/genética , Reflexo Anormal/fisiologia , Deleção de Sequência
6.
Fortschr Neurol Psychiatr ; 88(6): 403-415, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32557468

RESUMO

Huntington's disease was an important example for discussing the problem of predictive genetic testing. Like other movement disorders, it includes non-motor symptoms and a prodromal phase. As a rapidly progressive monogenetic disease, it is an important model disease for the study of neurodegenerative pathomechanisms and one of the first movement disorders for which causal therapies seem to be reachable.


Assuntos
Doença de Huntington , Testes Genéticos , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Doença de Huntington/terapia , Sintomas Prodrômicos
7.
Am J Physiol Cell Physiol ; 319(1): C218-C232, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432924

RESUMO

Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction for which only palliative treatment is currently available. Previously, we discovered reduced skeletal muscle Cl- channel (ClC-1) and inwardly rectifying K+ channel (Kir) currents in R6/2 HD transgenic mice. To further investigate the role of ClC-1 and Kir currents in HD skeletal muscle pathology, we measured the effect of reduced ClC-1 and Kir currents on action potential (AP) repetitive firing in R6/2 mice using a two-electrode current clamp. We found that R6/2 APs had a significantly lower peak amplitude, depolarized maximum repolarization, and prolonged decay time compared with wild type (WT). Of these differences, only the maximum repolarization was accounted for by the reduction in ClC-1 and Kir currents, indicating the presence of additional ion channel defects. We found that both KV1.5 and KV3.4 mRNA levels were significantly reduced in R6/2 skeletal muscle compared with WT, which explains the prolonged decay time of R6/2 APs. Overall, we found that APs in WT and R6/2 muscle significantly and progressively change during activity to maintain peak amplitude despite buildup of Na+ channel inactivation. Even with this resilience, the persistently reduced peak amplitude of R6/2 APs is expected to result in earlier fatigue and may help explain the motor impersistence experienced by HD patients. This work lays the foundation to link electrical changes to force generation defects in R6/2 HD mice and to examine the regulatory events controlling APs in WT muscle.


Assuntos
Potenciais de Ação/fisiologia , Modelos Animais de Doenças , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Músculo Esquelético/fisiopatologia , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos
8.
Fortschr Neurol Psychiatr ; 88(10): 661-667, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32369858

RESUMO

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a gene mutation in chromosome 4 that leads to an expansion of CAG - triplet repeats. It occurs mainly between the age of 30 and 50. Only less than 10 % of HD patients are younger than 20 years. In contrast to adult patients young HD patients show more often psychiatric and cognitive symptoms at disease onset than chorea. One third of the children with HD develops an epilepsy.We present 6 children diagnosed with HD in different stages of childhood. We describe first symptoms as well as genetic characteristics and other distinctive features.Both, the clinical presentation and the course of HD in childhood differ from HD in adults. In adolescents the clinical symptoms at onset are often psychiatric (like depression or attention deficit disorder). Choreatic movements typical for adult HD patients are missing.Due to the low prevalence of HD in childhood and the variability of clinical symptoms the process of diagnosing HD in children is difficult. Very often the diagnosis is made years after the first symptoms. Early diagnosis, however, is often important for managing social problems and problems in school.


Assuntos
Coreia , Doença de Huntington , Adolescente , Idade de Início , Criança , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Mutação , Repetições de Trinucleotídeos
9.
Sci Rep ; 10(1): 6875, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327686

RESUMO

One of the pathways of the unfolded protein response, initiated by PKR-like endoplasmic reticulum kinase (PERK), is key to neuronal homeostasis in neurodegenerative diseases. PERK pathway activation is usually accomplished by inhibiting eIF2α-P dephosphorylation, after its phosphorylation by PERK. Less tried is an approach involving direct PERK activation without compromising long-term recovery of eIF2α function by dephosphorylation. Here we show major improvement in cellular (STHdhQ111/111) and mouse (R6/2) Huntington's disease (HD) models using a potent small molecule PERK activator that we developed, MK-28. MK-28 showed PERK selectivity in vitro on a 391-kinase panel and rescued cells (but not PERK-/- cells) from ER stress-induced apoptosis. Cells were also rescued by the commercial PERK activator CCT020312 but MK-28 was significantly more potent. Computational docking suggested MK-28 interaction with the PERK activation loop. MK-28 exhibited remarkable pharmacokinetic properties and high BBB penetration in mice. Transient subcutaneous delivery of MK-28 significantly improved motor and executive functions and delayed death onset in R6/2 mice, showing no toxicity. Therefore, PERK activation can treat a most aggressive HD model, suggesting a possible approach for HD therapy and worth exploring for other neurodegenerative disorders.


Assuntos
Ativadores de Enzimas/farmacologia , Doença de Huntington/enzimologia , eIF-2 Quinase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativadores de Enzimas/química , Fator de Iniciação 2 em Eucariotos/metabolismo , Proteína Huntingtina/metabolismo , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Camundongos , Modelos Biológicos , Neostriado/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida
10.
PLoS Comput Biol ; 16(4): e1007648, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32302302

RESUMO

Medium spiny neurons (MSNs) comprise over 90% of cells in the striatum. In vivo MSNs display coherent burst firing cell assembly activity patterns, even though isolated MSNs do not burst fire intrinsically. This activity is important for the learning and execution of action sequences and is characteristically dysregulated in Huntington's Disease (HD). However, how dysregulation is caused by the various neural pathologies affecting MSNs in HD is unknown. Previous modeling work using simple cell models has shown that cell assembly activity patterns can emerge as a result of MSN inhibitory network interactions. Here, by directly estimating MSN network model parameters from single unit spiking data, we show that a network composed of much more physiologically detailed MSNs provides an excellent quantitative fit to wild type (WT) mouse spiking data, but only when network parameters are appropriate for the striatum. We find the WT MSN network is situated in a regime close to a transition from stable to strongly fluctuating network dynamics. This regime facilitates the generation of low-dimensional slowly varying coherent activity patterns and confers high sensitivity to variations in cortical driving. By re-estimating the model on HD spiking data we discover network parameter modifications are consistent across three very different types of HD mutant mouse models (YAC128, Q175, R6/2). In striking agreement with the known pathophysiology we find feedforward excitatory drive is reduced in HD compared to WT mice, while recurrent inhibition also shows phenotype dependency. We show that these modifications shift the HD MSN network to a sub-optimal regime where higher dimensional incoherent rapidly fluctuating activity predominates. Our results provide insight into a diverse range of experimental findings in HD, including cognitive and motor symptoms, and may suggest new avenues for treatment.


Assuntos
Corpo Estriado/fisiologia , Doença de Huntington/fisiopatologia , Animais , Mapeamento Encefálico , Modelos Animais de Doenças , Progressão da Doença , Neurônios GABAérgicos/metabolismo , Homozigoto , Humanos , Proteína Huntingtina/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Neurônios/fisiologia , Fenótipo , Radiocirurgia
11.
Psychiatry Res Neuroimaging ; 298: 111048, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32120305

RESUMO

In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.


Assuntos
Disfunção Cognitiva/fisiopatologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Tálamo/patologia , Adulto , Atrofia/patologia , Disfunção Cognitiva/etiologia , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico por imagem , Imagem por Ressonância Magnética , Tálamo/diagnóstico por imagem
13.
PLoS One ; 15(2): e0228081, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040519

RESUMO

The basal ganglia (BG) is a collection of nuclei located deep beneath the cerebral cortex that is involved in learning and selection of rewarded actions. Here, we analyzed BG mechanisms that enable these functions. We implemented a rate model of a BG-thalamo-cortical loop and simulated its performance in a standard action selection task. We have shown that potentiation of corticostriatal synapses enables learning of a rewarded option. However, these synapses became redundant later as direct connections between prefrontal and premotor cortices (PFC-PMC) were potentiated by Hebbian learning. After we switched the reward to the previously unrewarded option (reversal), the BG was again responsible for switching to the new option. Due to the potentiated direct cortical connections, the system was biased to the previously rewarded choice, and establishing the new choice required a greater number of trials. Guided by physiological research, we then modified our model to reproduce pathological states of mild Parkinson's and Huntington's diseases. We found that in the Parkinsonian state PMC activity levels become extremely variable, which is caused by oscillations arising in the BG-thalamo-cortical loop. The model reproduced severe impairment of learning and predicted that this is caused by these oscillations as well as a reduced reward prediction signal. In the Huntington state, the potentiation of the PFC-PMC connections produced better learning, but altered BG output disrupted expression of the rewarded choices. This resulted in random switching between rewarded and unrewarded choices resembling an exploratory phase that never ended. Along with other computational studies, our results further reconcile the apparent contradiction between the critical involvement of the BG in execution of previously learned actions and yet no impairment of these actions after BG output is ablated by lesions or deep brain stimulation. We predict that the cortico-BG-thalamo-cortical loop conforms to previously learned choice in healthy conditions, but impedes those choices in disease states.


Assuntos
Gânglios da Base/fisiologia , Gânglios da Base/fisiopatologia , Doença de Huntington/fisiopatologia , Aprendizagem , Modelos Neurológicos , Doença de Parkinson/fisiopatologia , Recompensa , Estudos de Casos e Controles , Córtex Cerebral/fisiologia , Córtex Cerebral/fisiopatologia , Humanos , Plasticidade Neuronal/fisiologia
14.
Neurology ; 94(5): 217-228, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31907286

RESUMO

OBJECTIVE: In the past decade, an increasing number of studies have examined the efficacy of physical therapy interventions in people with Huntington disease (HD). METHODS: We performed a mixed-methods systematic review using Joanna Briggs Institute (JBI) methodology and included experimental and observational study designs. The search resulted in 23 quantitative studies and 3 qualitative studies from which we extracted data using JBI standardized extraction tools. Results of this review suggested that physical therapy interventions may improve motor impairments and activity limitations in people with HD. Here, we expand on the review findings to provide specific recommendations to guide clinical practice. RESULTS: We recommend the following specific physical therapy interventions for people with HD: aerobic exercise (grade A evidence), alone or in combination with resistance training to improve fitness and motor function, and supervised gait training (grade A evidence) to improve spatiotemporal features of gait. In addition, there is weak (grade B) evidence that exercise training improves balance but does not show a reduction in the frequency of falls; inspiratory and expiratory training improves breathing function and capacity; and training of transfers, getting up from the floor, and providing strategies to caregivers for involvement in physical activity in the midstages of HD may improve performance. There is expert consensus for the use of positioning devices, seating adaptations, and caregiver training in late stages of HD. CONCLUSIONS: There is strong evidence to support physical therapy interventions to improve fitness, motor function, and gait in persons with HD.


Assuntos
Doença de Huntington/reabilitação , Modalidades de Fisioterapia , Acidentes por Quedas/prevenção & controle , Exercícios Respiratórios , Cuidadores/educação , Exercício Físico , Humanos , Doença de Huntington/fisiopatologia , Movimentação e Reposicionamento de Pacientes , Guias de Prática Clínica como Assunto , Treinamento de Resistência
15.
Neuron ; 105(5): 813-821.e6, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31899071

RESUMO

Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Relacionadas à Autofagia/genética , Doença de Huntington/genética , Macroautofagia/genética , Neurônios/metabolismo , Agregação Patológica de Proteínas/genética , Idade de Início , Animais , Morte Celular/genética , Modelos Animais de Doenças , Feminino , Fibroblastos , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/fisiopatologia
16.
PLoS One ; 15(1): e0226827, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910203

RESUMO

Huntington's disease (HD) is characterized by motor, cognitive, and psychiatric dysfunction. HD progression causes loss of automaticity, such that previously automatic tasks require greater attentional resources. Dual-task (DT) paradigms and fast-paced gait may stress the locomotor system, revealing deficits not seen under single-task (ST). However, the impact of gait "stress tests" on HD individuals needs further investigation. Therefore, the aims of this study were to investigate whether: 1) fast-paced and dual-task walking uncover deficits in gait and turning not seen under single-task, 2) cognitive and gait outcomes relate to fall incidence, and 3) gait deficits measured with wearable inertial sensors correlate with motor symptom severity in HD as measured by the Unified Huntington's disease Rating Scale-total motor score (UHDRS-TMS). Seventeen HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative gait testing via a 25m, two-minute walk test with APDMTM inertial sensors. Gait was assessed under a 1) ST, self-selected pace, 2) fast-as-possible (FAP) pace, and 3) verbal fluency DT. The UHDRS-TMS and a cognitive test battery were administered, and a retrospective fall history was obtained. During ST, DT, and FAP conditions, HD participants demonstrated slower gait, shorter stride length, and greater lateral step and stride length variability compared to controls (p<0.00001 to 0.034). Significant dual-task costs (DTC) were observed for turns; HD participants took more time (p = 0.013) and steps (p = 0.028) to complete a turn under DT compared to controls. Higher UHDRS-TMS correlated with greater stride length variability, less double-support, and more swing-phase time under all conditions. Decreased processing speed was associated with increased gait variability under ST and FAP conditions. Unexpectedly, participant's self-reported falls did not correlate with any gait or turn parameters. HD participants demonstrated significantly greater DTC for turning, which is less automatic than straight walking, requiring coordination of body segments, anticipatory control, and cortical regulation. Turn complexity likely makes it more susceptible to cognitive interference in HD.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Huntington/psicologia , Idoso , Estudos de Casos e Controles , Feminino , Marcha , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/psicologia , Humanos , Doença de Huntington/complicações , Doença de Huntington/fisiopatologia , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor , Estudos Retrospectivos , Teste de Caminhada
17.
Sci Rep ; 10(1): 1252, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988371

RESUMO

Patient stratification is critical for the sensitivity of clinical trials at early stages of neurodegenerative disorders. In Huntington's disease (HD), genetic tests make cognitive, motor and brain imaging measurements possible before symptom manifestation (pre-HD). We evaluated pre-HD stratification models based on single visit resting-state functional MRI (rs-fMRI) data that assess observed longitudinal motor and cognitive change rates from the multisite Track-On HD cohort (74 pre-HD, 79 control participants). We computed longitudinal performance change on 10 tasks (including visits from the preceding TRACK-HD study when available), as well as functional connectivity density (FCD) maps in single rs-fMRI visits, which showed high test-retest reliability. We assigned pre-HD subjects to subgroups of fast, intermediate, and slow change along single tasks or combinations of them, correcting for expectations based on aging; and trained FCD-based classifiers to distinguish fast- from slow-progressing individuals. For robustness, models were validated across imaging sites. Stratification models distinguished fast- from slow-changing participants and provided continuous assessments of decline applicable to the whole pre-HD population, relying on previously-neglected white matter functional signals. These results suggest novel correlates of early deterioration and a robust stratification strategy where a single MRI measurement provides an estimate of multiple ongoing longitudinal changes.


Assuntos
Disfunção Cognitiva/diagnóstico por imagem , Doença de Huntington/classificação , Doença de Huntington/fisiopatologia , Adulto , Encéfalo/patologia , Mapeamento Encefálico/métodos , Estudos de Casos e Controles , Transtornos Cognitivos/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Doença de Huntington/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Exame Neurológico/métodos , Descanso
18.
Arch Clin Neuropsychol ; 35(4): 358-364, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31813981

RESUMO

OBJECTIVE: Patients with Huntington's disease (HD) may show impairments of frontal cortical-subcortical circuits with difficulties on cognitive flexibility tasks. One marker of poor flexibility is "perseveration" behavior, which refers to inappropriate and involuntary production of iterative responses not adequate to the current task demands. This study explored frequency, type, and possible cognitive mechanisms of verbal perseverations in a large sample of HD patients. METHOD: A sample of 128 patients with HD underwent phonological and category verbal fluency tests to assess perseverative errors, within a wide neuropsychological, psychopathological, motor, and functional assessment. RESULTS: Perseverative errors in verbal fluency task occurred in 89 (69.5%) patients. Patients showing perseverations scored significantly lower than patients without perseverations on tasks tapping executive and motor functions and on functional independence scales. Logistic regression analysis revealed a significant independent association of verbal perseverations with scores on Trail Making Test only. Conclusions: Verbal perseverations are frequent in HD patients and are likely related with impairments of attentional switching and working memory, hampering tracking of verbal responses already produced. Perseverative behavior may serve as a useful clinical marker of cognitive and functional impairment in patients with HD.


Assuntos
Atenção , Doença de Huntington , Comportamento Verbal , Humanos , Doença de Huntington/complicações , Doença de Huntington/fisiopatologia , Memória de Curto Prazo , Testes Neuropsicológicos , Estudos Retrospectivos
19.
Chem Biol Interact ; 315: 108907, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31778667

RESUMO

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine (CAG) expansion in the Huntingtin (HTT) gene. The CAG140 knock-in (KI) mouse model recapitulates the progression of motor symptoms emerging at 12 months of age. OBJECTIVE: This study was aimed at assessing the effects of exercise, in the form of treadmill running, and examining its impact on motor behavior and markers of metabolism in the CAG140 KI mouse model of HD after motor symptoms have emerged. METHODS: CAG140 KI mice at 13-15 months of age were subjected to treadmill exercise 3 days per week for 1 h per day or remained sedentary. After 12 weeks of exercise brain tissues were analyzed for enzymatic activity including mitochondria Complexes I, II/III, and IV, transglutaminase, aconitase, pyruvate dehydrogenase, and phosphofructokinase1/2. In addition, the concentration was determined for nitrate/nitrite, pyruvate carboxylase, NAD+/NADH, and glutamate as well as the ratio of mitochondria and nuclear DNA. Motor behavior was tested using the rotarod. RESULTS: Exercise resulted in increased [nitrite + nitrate] levels (surmised as nitric oxide), reduced transglutaminase activity, increased aconitase activity with increased tricarboxylic acid-generated reducing equivalents and mitochondrial oxidative phosphorylation complexes activity. Mitochondrial function was strengthened by increases in glycolysis, pyruvate dehydrogenase activity, and anaplerosis component represented by pyruvate carboxylase. CONCLUSIONS: These changes in mitochondrial function were associated with improved motor performance on the rotarod test. These findings suggest that exercise may have beneficial effects on motor behavior by reversing deficits in mitochondrial function in a rodent model of HD.


Assuntos
Comportamento Animal/fisiologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Atividade Motora/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Teste de Esforço/métodos , Feminino , Doença de Huntington/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Ácidos Tricarboxílicos/metabolismo
20.
Ann Neurol ; 87(2): 246-255, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31725947

RESUMO

OBJECTIVE: Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease-modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms that potentially could be used as a target therapeutically. METHODS: Lymphocyte activity in cerebrospinal fluid (CSF) from 4 cohorts of HTT gene expansion carriers (n = 121 in total) and controls was analyzed by techniques based on flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The data of this study provide evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers, we found increased levels of proinflammatory cytokines, including IL-17, and increased consumption of the lymphocyte growth factor IL-7 before motor onset of HD. In concordance, we observed an increased prevalence of IL-17-producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre-motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers. INTERPRETATION: These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T -cell-driven inflammation before motor onset might be of benefit in HTT gene expansion carriers. ANN NEUROL 2020;87:246-255.


Assuntos
Doença de Huntington/imunologia , Doença de Huntington/fisiopatologia , Ativação Linfocitária/imunologia , Células Th17/imunologia , Adulto , Idoso , Proliferação de Células , Citocinas/líquido cefalorraquidiano , Citocinas/metabolismo , Feminino , Heterozigoto , Humanos , Proteína Huntingtina/genética , Doença de Huntington/líquido cefalorraquidiano , Doença de Huntington/genética , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Células Th17/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
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