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1.
Sci Rep ; 12(1): 20285, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434031

RESUMO

SCAs are autosomal dominant neurodegenerative disorders caused by a gain-of-function protein with toxic activities, containing an expanded polyQ tract in the coding region. There are no treatments available to delay the onset, stop or slow down the progression of these pathologies. In this work we focus our attention on SCA1 which is one of the most common genotypes circulating in Italy. Here, we develop a CRISPR/Cas9-based approach to reduce both forms of the ATXN1 protein, normal and mutated with expanded polyQ. We started with the screening of 10 different sgRNAs able to target Exon 8 of the ATXN1 gene. The two most promising sgRNAs were validated in fibroblasts isolated from SCA1 patients, following the identification of the best transfection method for this type of cell. Our silencing approach significantly downregulated the expression of ataxin1, due to large deletions and the introduction of small changes in the ATXN1 gene, evidenced by NGS analysis, without major effects on cell viability. Furthermore, very few significant guide RNA-dependent off-target effects were observed. These preliminary results not only allowed us to identify the best transfection method for SCA1 fibroblasts, but strongly support CRISPR/Cas9 as a promising approach for the treatment of expanded polyQ diseases. Further investigations will be needed to verify the efficacy of our silencing system in SCA1 neurons and animal models.


Assuntos
Ataxias Espinocerebelares , Animais , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Ataxias Espinocerebelares/metabolismo , Mutação com Ganho de Função , Sistemas CRISPR-Cas , Ataxina-1/genética , Ataxina-1/metabolismo , Itália
2.
Clin Neurol Neurosurg ; 223: 107503, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36368168

RESUMO

BACKGROUND: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion detection with long-read sequencing (LRS) feasible. Our study investigated one family with SCA 36 and further summarized the genetic and clinical characteristics of the total of 161 patients across different ethnic groups reported worldwide. METHODS: We enrolled a pedigree of 4 patients. The proband was a 55-year-old male. And he was screened for dynamic mutations of SCA subtypes by Tri-prime PCR (TP-PCR) and capillary electrophoresis, showing NOP56 as the candidate gene. The cosegregation was conducted by screening the NOP56 gene in his daughter and further confirmed by low-coverage (∼15 ×) LRS on the Oxford Nanopore platform. RESULTS: The SCA36 pedigree included a total of 4 patients. The proband showed the initial manifestation at the age of 45 years old, which was characterized by truncal ataxia. Genetic test results showed the (GGCCTG)n expansion in NOP56 gene (3/>15 and 6/>15 times respectively). To clarify the diagnosis genetically, LRS was performed in his daughter showing a large intronic insertion (chr20: 2633004 INS 7603 bp) containing (GGCCTG)n expansion of 782 units in NOP56 as the causative mutation. CONCLUSIONS: We identified one SCA36 pedigree by combining TP-PCR with LRS. Our study suggested LRS as an effective tool for molecular diagnosis. LRS also worked as a supplementary but necessary diagnostic tool for dynamic mutation-related SCA on the basis of repeat-primed PCR as well as capillary electrophoresis.


Assuntos
Proteínas Nucleares , Ataxias Espinocerebelares , Masculino , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Íntrons , Linhagem , Ataxia/genética
3.
Proc Natl Acad Sci U S A ; 119(48): e2212659119, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36409883

RESUMO

Platelets play a role not only in hemostasis and thrombosis, but also in inflammation and innate immunity. We previously reported that an activated form of tyrosyl-tRNA synthetase (YRSACT) has an extratranslational activity that enhances megakaryopoiesis and platelet production in mice. Here, we report that YRSACT mimics inflammatory stress inducing a unique megakaryocyte (MK) population with stem cell (Sca1) and myeloid (F4/80) markers through a mechanism dependent on Toll-like receptor (TLR) activation and type I interferon (IFN-I) signaling. This mimicry of inflammatory stress by YRSACT was studied in mice infected by lymphocytic choriomeningitis virus (LCMV). Using Sca1/EGFP transgenic mice, we demonstrated that IFN-I induced by YRSACT or LCMV infection suppressed normal hematopoiesis while activating an alternative pathway of thrombopoiesis. Platelets of inflammatory origin (Sca1/EGFP+) were a relevant proportion of those circulating during recovery from thrombocytopenia. Analysis of these "inflammatory" MKs and platelets suggested their origin in myeloid/MK-biased hematopoietic stem cells (HSCs) that bypassed the classical MK-erythroid progenitor (MEP) pathway to replenish platelets and promote recovery from thrombocytopenia. Notably, inflammatory platelets displayed enhanced agonist-induced activation and procoagulant activities. Moreover, myeloid/MK-biased progenitors and MKs were mobilized from the bone marrow, as evidenced by their presence in the lung microvasculature within fibrin-containing microthrombi. Our results define the function of YRSACT in platelet generation and contribute to elucidate platelet alterations in number and function during viral infection.


Assuntos
Ataxias Espinocerebelares , Trombocitopenia , Trombose , Tirosina-tRNA Ligase , Viroses , Camundongos , Animais , Trombopoese , Camundongos Transgênicos
4.
J Neurol Sci ; 443: 120493, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36410186

RESUMO

The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and balance, peripheral neuropathy, impaired vision, incontinence, respiratory insufficiency, dysphagia, and dysarthria. Although many patients with SCA have respiratory-related complications, the exact mechanism and extent of this pathology remain unclear. This review aims to provide an update on the recent clinical and preclinical scientific findings on neuropathology causing respiratory insufficiency in SCA.


Assuntos
Transtornos de Deglutição , Neurologia , Insuficiência Respiratória , Ataxias Espinocerebelares , Humanos , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Disartria
5.
BMC Neurol ; 22(1): 381, 2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209056

RESUMO

BACKGROUND: Turner syndrome (TS) is a rare condition associated with a completely or partially missing X chromosome that affects 1 in 2500 girls. TS increases the risk of autoimmune diseases, including Graves' disease (GD). Moyamoya disease is a rare cerebral arteriopathy of unknown etiology characterized by progressive bilateral stenosis of the internal carotid artery and its branches. Both TS and GD have been associated with Moyamoya. Type 2 spinocerebellar ataxia (SCA2) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in ATXN2. We present the first case of Moyamoya syndrome in a patient with a previous diagnosis of TS and GD who tested positive for SCA2 and had imaging findings compatible with an overlap of SCA2 and Moyamoya. CASE PRESENTATION: A 43-year-old woman presented with mild gait imbalance for 2 years. Her family history was positive for type 2 spinocerebellar ataxia (SCA2). She had been diagnosed with Turner Syndrome (45,X) and Graves disease three years before. Brain MRI revealed bilateral frontal and parietal cystic encephalomalacia in watershed zones, atrophy of pons, middle cerebellar peduncles and cerebellum. MR angiography showed progressive stenosis of both internal carotid arteries with lenticulostriate collaterals, suggestive of Moya-Moya disease. Molecular analysis confirmed the diagnosis of SCA2. CONCLUSIONS: With increased availability of tools for genetic diagnosis, physicians need to be aware of the possibility of a single patient presenting two or more rare diseases. This report underscores the modern dilemmas created by increasingly accurate imaging techniques and available and extensive genetic testing.


Assuntos
Doença de Moyamoya , Ataxias Espinocerebelares , Síndrome de Turner , Adulto , Constrição Patológica , Feminino , Humanos , Doença de Moyamoya/complicações , Doença de Moyamoya/diagnóstico por imagem , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Síndrome de Turner/complicações
6.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233198

RESUMO

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.


Assuntos
Ataxina-2 , Ataxias Espinocerebelares , Animais , Ataxina-2/genética , Ataxina-2/metabolismo , Ataxina-3/genética , Caspase 3/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , RNA Mensageiro , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Ataxias Espinocerebelares/patologia
7.
Cells ; 11(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36291186

RESUMO

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.


Assuntos
Astrócitos , Ataxias Espinocerebelares , Camundongos , Animais , Ataxina-1/genética , Ataxina-1/metabolismo , Astrócitos/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Cerebelo/metabolismo , Fenótipo
8.
Artigo em Inglês | MEDLINE | ID: mdl-36303814

RESUMO

Background: The significance of falls and their repercussions in Parkinson's disease has been extensively researched. However, despite potentially serious effects on health and quality of life and negative impact on the healthcare system, there is not a sufficient understanding of the role of falls in hyperkinetic movement disorders (HKMDs). This review aims to provide an overview of the prevalence of falls, injuries, and preventive measures in the most common HKMDs. Methods: Studies up to May 1, 2022 were searched in PubMed using Medical Subjects Headings of relatively prevalent HKMDs associated with the terms "accidental falls", "injuries", "fractures", and "accident prevention". Results: In our review of 37 studies out of 155, we found evidence that for several HKMDs, such as spinocerebellar ataxia, essential tremor, Huntington's disease, and dystonia, fall risk is increased. Falls were reported in up to 84% of spinocerebellar ataxia patients, 59% of essential tremor patients, and 79% of Huntington's patients, with 65% of the latter falling frequently. Injuries occurred in up to 73% in Huntington and 74% in ataxia patients. Most of the common diseases characterized by HKMDs were investigated for both fall causes and consequences, but prevention studies were limited to spinocerebellar ataxia and Huntington's disease. Discussion: The limited available data suggest that patients with several HKMDs can be considered to be at increased risk of falling and that the consequences can be serious. As a result, physicians should be advised to include fall exploration in their routine workup and provide advice for safer mobility. In general, more research into fall-related concerns in HKMDs is necessary. Highlights: In contrast to Parkinson's disease, the prevalence of accidental falls, their repercussions, and preventive strategies are under-investigated in hyperkinetic movement disorders (HKMDs). Several HKMDs such as essential tremor, ataxia, and Huntington's disease have reported fall rates of up to 84% and fall-related injury rates of up to 74%. Therefore, routine examinations of HKMD patients should include a fall exploration and provide advice on safe mobility.


Assuntos
Tremor Essencial , Doença de Huntington , Doença de Parkinson , Ataxias Espinocerebelares , Humanos , Acidentes por Quedas/prevenção & controle , Hipercinese , Qualidade de Vida , Ataxia
9.
Cell Rep ; 41(4): 111505, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36288715

RESUMO

Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.


Assuntos
Esclerose Amiotrófica Lateral , Ataxias Espinocerebelares , Animais , Camundongos , Humanos , Ataxina-2/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , RNA Interferente Pequeno , Receptores Nogo/metabolismo , Ataxias Espinocerebelares/genética , Camundongos Knockout , Peptídeos/metabolismo , Proteínas Nogo/genética , Proteínas Nogo/metabolismo
10.
Cell Rep ; 41(4): 111508, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36288714

RESUMO

Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.


Assuntos
Esclerose Amiotrófica Lateral , Ataxias Espinocerebelares , ATPases Vacuolares Próton-Translocadoras , Animais , Humanos , Camundongos , Ataxina-2/genética , Ataxina-2/metabolismo , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Preparações Farmacêuticas , Ácido Etidrônico , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Oligonucleotídeos Antissenso/genética
11.
Sensors (Basel) ; 22(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36298343

RESUMO

The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient's wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the cycles of the finger-to-nose test (FNT). We extracted multiple features from the detected cycles and identified features and parameters correlated with the SARA scores. Additionally, we developed models to predict the severity of symptoms based on the FNT. The proposed technique was validated on a dataset comprising the seventeen (n = 17) participants' assessments. The cycle detection technique showed an accuracy of 97.6% in a Bland-Altman analysis and a 94% accuracy (F1-score of 0.93) in predicting the severity of the FNT. Furthermore, the dependency of the upper-extremity tests was investigated through statistical analysis, and the results confirm dependency and potential redundancies in the upper-extremity SARA assessments. Our findings pave the way to enhance the utility of objective measures of SCA assessments. The proposed wearable-based platform has the potential to eliminate subjectivity and inter-rater variabilities in assessing ataxia.


Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Dispositivos Eletrônicos Vestíveis , Humanos , Ataxias Espinocerebelares/diagnóstico , Ataxia Cerebelar/diagnóstico , Ataxia/diagnóstico , Extremidade Superior
12.
Orphanet J Rare Dis ; 17(1): 369, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36183078

RESUMO

BACKGROUND: Autosomal recessive cerebellar ataxias (ARCA) are a group of rare inherited disorders characterized by degeneration or abnormal development of the cerebellum. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is one of the most prevalent in Europe. OBJECTIVES: The aim of this study is to provide a better understanding of the manifestations and impacts of ARSACS. METHODS: A systematic review of the literature was conducted, followed by a qualitative study using semistructured interviews and discussion groups to obtain the experience of people affected. RESULTS: According to the PROMIS framework, the results show manifestations and impacts in three components of health: physical, mental, and social. Fatigue and struggles with balance and dexterity are the physical manifestations of the disease most often cited by participants. Negative affects such as frustration and depression are among the mental health impacts with some loss in cognitive abilities. Social health is the least documented component; nonetheless, people with the disease report significant impacts in terms of social relationships, activities and work. CONCLUSIONS: These findings shed new light on the experience of people with recessive ataxia and identify key aspects to assess to improve their overall health.


Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Ataxia , Humanos , Deficiência Intelectual , Espasticidade Muscular/genética , Mutação , Atrofia Óptica , Medidas de Resultados Relatados pelo Paciente , Ataxias Espinocerebelares/congênito , Ataxias Espinocerebelares/genética
13.
Clin Neurol Neurosurg ; 222: 107473, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36252335

RESUMO

OBJECTIVE: We aimed to analyze the occurrence and clinical and genetic characteristics of spinocerebellar ataxia type 17 (SCA17) among Russian patients with progressive cerebellar ataxia or Huntington disease-like phenotype. METHODS: Genetic analysis of CAG/CAA repeats in TBP gene was carried out in 217 patients, including 153 patients with progressive unspecified ataxia and 64 patients with Huntington disease-like phenotype. SCA types 1, 2, 3, 6 and 8, Friedreich's ataxia, CANVAS and Huntington disease were preliminarily excluded. RESULTS: Six unrelated patients with SCA17 (2.8 %) were identified (43-57 CAG/CAA repeats in TBP gene). Two patients had a positive family history. Age at the disease onset ranged from 15 to 47 years. The core clinical syndrome included progressive cerebellar ataxia, dysarthria, movement disorders, cognitive impairment, and psychiatric symptoms. One patient had epilepsy with rare generalized tonic-clonic seizures. Another patient with diffuse muscle atrophy and small expansion size (43 CAG/CAA repeats) had myopathic changes in skeletal muscles on EMG study. We also described a patient with a large expansion size of 57 CAA/CAG repeats with early onset and rapid disease progression. CONCLUSION: SCA17 is a relatively rare cause of progressive disorders with ataxia and chorea, but it should be considered in the spectrum of differential diagnosis in such patients. Most of our SCA17 cases were sporadic which should be kept in mind when planning genetic testing in patients with spinocerebellar ataxia and chorea.


Assuntos
Ataxia Cerebelar , Coreia , Doença de Huntington , Ataxias Espinocerebelares , Humanos , Doença de Huntington/genética , Ataxia Cerebelar/genética , Coreia/genética , TATA Box , Ataxias Espinocerebelares/genética , Fenótipo , Ataxia/genética , Mutação/genética
14.
PLoS One ; 17(10): e0275580, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36251631

RESUMO

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by a trinucleotide CAG repeat. SCA7 predominantly causes a loss of photoreceptors in the retina and Purkinje cells of the cerebellum. Severe infantile-onset SCA7 also causes renal and cardiac irregularities. Previous reports have shown that SCA7 results in increased susceptibility to DNA damage. Since DNA damage can lead to accumulation of senescent cells, we hypothesized that SCA7 causes an accumulation of senescent cells over the course of disease. A 140-CAG repeat SCA7 mouse model was evaluated for signs of disease-specific involvement in the kidney, heart, and cerebellum, tissues that are commonly affected in the infantile form. We found evidence of significant renal abnormality that coincided with an accumulation of senescent cells in the kidneys of SCA7140Q/5Q mice, based on histology findings in addition to RT-qPCR for the cell cycle inhibitors p16Ink4a and p21Cip1 and senescence-associated ß-galactosidase (SA-ßgal) staining, respectively. The Purkinje layer in the cerebellum of SCA7140Q/5Q mice also displayed SA-ßgal+ cells. These novel findings offer evidence that senescent cells accumulate in affected tissues and may possibly contribute to SCA7's specific phenotype.


Assuntos
Proteínas do Tecido Nervoso , Ataxias Espinocerebelares , Animais , Ataxina-7/genética , Modelos Animais de Doenças , Galactosidases , Camundongos , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Repetições de Trinucleotídeos
15.
Genes (Basel) ; 13(9)2022 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-36140834

RESUMO

Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We investigated a consanguineous Pakistani family with four patients partially presenting with clinical features of SCAR13 using whole exome sequencing. Segregation analysis was performed by Sanger sequencing in all the available individuals of the family. Results: Patients presented with quadrupedal gait, delayed developmental milestones, non-progressive peripheral neuropathy, and cognitive impairment. Whole exome sequencing identified a novel pathogenic nonsense homozygous variant, Gly240*, in the gene GRM1 as a cause of SCAR13 that segregates with the recessive disease. Discussion: We report a novel homozygous nonsense variant in the GRM1 gene in four Pakistani patients presenting with clinical features that partially overlap with the already reported phenotype of SCAR13. In addition, the family presented quadrupedal gait and non-progressive symptoms, manifestations which have not been recognized previously. So far, only four variants in GRM1 have been reported, in families of Roma, Iranian, and Tunisian origins. The current study adds to the mutation spectrum of GRM1 and provides a rare presentation of SCAR13, the first from the Pakistani population.


Assuntos
Ataxias Espinocerebelares , Humanos , Irã (Geográfico) , Paquistão , Linhagem , Ataxias Espinocerebelares/congênito , Ataxias Espinocerebelares/genética
16.
Stem Cell Res ; 64: 102904, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36055117

RESUMO

Human Kinesin Family Member 5A (KIF5A) gene mutations have been identified as a putative genetic cause of amyotrophic lateral sclerosis (ALS). Disease modelling using human-induced pluripotent stem cells (HiPSCs) is the next-generation approach to studying numerous human diseases. For the current investigation, we report the generation of patient-specific KIF5A iPSC lines with a mutation at the splice site mutation (c.3020 + 3 A > T) in the intronic region. The resulting line displayed markers for pluripotency, a healthy karyotype, the ability to differentiate into three germ layers in vitro, vector clearance, the KIF5A mutation, STR-based genomic identity, and contamination-free culture.


Assuntos
Esclerose Amiotrófica Lateral , Células-Tronco Pluripotentes Induzidas , Ataxias Espinocerebelares , Humanos , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Cinesinas/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Ataxias Espinocerebelares/metabolismo , Linhagem Celular , Mutação/genética , Fenótipo , Paraplegia/metabolismo , Família
17.
Intern Med ; 61(18): 2793-2796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36104177

RESUMO

We herein report a 61-year-old woman who was genetically diagnosed with spinocerebellar ataxia type 31 whose symptoms were modified by anti-amino terminal of alpha-enolase (NAE) antibodies, known as a biomarker of Hashimoto's encephalopathy (HE), and ultimately responded to immunotherapy. The relative titers of anti-NAE antibodies increased when her cerebellar ataxia showed acute deterioration and decreased after immunotherapy. This is the first report of cerebellar ataxia associated with genetic spinocerebellar ataxia with concomitant cerebellar type HE. Physicians should be mindful of measuring anti-NAE antibodies to prevent overlooking patients with genetic spinocerebellar ataxia with treatable simultaneous ataxic diseases.


Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Autoanticorpos , Ataxia Cerebelar/diagnóstico , Encefalite , Feminino , Doença de Hashimoto , Humanos , Pessoa de Meia-Idade , Fosfopiruvato Hidratase
18.
Cells ; 11(17)2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36078147

RESUMO

Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the CACNA1A gene that encodes the α1A subunit of the P/Q type voltage-gated Ca2+ channel. Mouse models of SCA6 demonstrate impaired locomotive function and reduced firing precision of cerebellar Purkinje in the anterior vermis. Here, to further assess deficits in other cerebellar-dependent behaviors, we characterized the oculomotor phenotype of a knock-in mouse model with hyper-expanded polyQ repeats (SCA684Q). We found a reduction in the efficacy of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) in SCA6 mutant mice, without a change in phase, compared to their litter-matched controls. Additionally, VOR motor learning was significantly impaired in SCA684Q mice. Given that the floccular lobe of the cerebellum plays a vital role in the generation of OKR and VOR calibration and motor learning, we investigated the firing behavior and morphology of floccular cerebellar Purkinje cells. Overall, we found a reduction in the firing precision of floccular lobe Purkinje cells but no morphological difference between SCA684Q and wild-type mice. Taken together, our findings establish that gaze stabilization and motor learning are impaired in SCA684Q mice and suggest that altered cerebellar output contributes to these deficits.


Assuntos
Ataxias Espinocerebelares , Degenerações Espinocerebelares , Animais , Cerebelo/metabolismo , Modelos Animais de Doenças , Camundongos , Células de Purkinje , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Degenerações Espinocerebelares/genética
19.
Cells ; 11(17)2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-36078042

RESUMO

The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to the progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well-known. Here, we characterized pathology in the motor cortex of a SCA1 mouse model and performed RNA sequencing in this brain region to investigate the impact of mutant ataxin-1 towards transcriptomic alterations. We identified progressive cortical pathology and significant transcriptomic changes in the motor cortex of a SCA1 mouse model. We also identified progressive, region-specific, colocalization of p62 protein with mutant ataxin-1 aggregates in broad brain regions, but not the cerebellum or brainstem. A cross-regional comparison of the SCA1 cortical and cerebellar transcriptomic changes identified both common and unique gene expression changes between the two regions, including shared synaptic dysfunction and region-specific kinase regulation. These findings suggest that the cortex is progressively impacted via both shared and region-specific mechanisms in SCA1.


Assuntos
Ataxina-1/metabolismo , Proteínas do Tecido Nervoso , Ataxias Espinocerebelares , Animais , Ataxina-1/genética , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Células de Purkinje , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia
20.
Sci Signal ; 15(753): eabk1147, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36166510

RESUMO

Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline variants in the diacylglycerol (DAG)/Ca2+-regulated protein kinase Cγ (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. Most of the identified mutations cluster in the DAG-sensing C1 domains. Here, we found with a FRET-based activity reporter that SCA14-associated PKCγ mutations, including a previously undescribed variant, D115Y, enhanced the basal activity of the kinase by compromising its autoinhibition. Unlike other mutations in PKC that impair its autoinhibition but lead to its degradation, the C1 domain mutations protected PKCγ from such down-regulation. This enhanced basal signaling rewired the brain phosphoproteome, as revealed by phosphoproteomic analysis of cerebella from mice expressing a human SCA14-associated H101Y mutant PKCγ transgene. Mutations that induced a high basal activity in vitro were associated with earlier average age of onset in patients. Furthermore, the extent of disrupted autoinhibition, but not agonist-stimulated activity, correlated with disease severity. Molecular modeling indicated that almost all SCA14 variants not within the C1 domain were located at interfaces with the C1B domain, suggesting that mutations in and proximal to the C1B domain are a susceptibility for SCA14 because they uniquely enhance PKCγ basal activity while protecting the enzyme from down-regulation. These results provide insight into how PKCγ activation is modulated and how deregulation of the cerebellar phosphoproteome by SCA14-associated mutations affects disease progression.


Assuntos
Diglicerídeos , Ataxias Espinocerebelares , Animais , Diglicerídeos/metabolismo , Humanos , Camundongos , Mutação , Proteína Quinase C , Células de Purkinje/metabolismo , Ataxias Espinocerebelares/genética
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