RESUMEN
Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Musculares , Distrofia Muscular de Cinturas , Distrofias Musculares , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ácido Mevalónico , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/diagnóstico , Enfermedades Musculares/genética , Oxidorreductasas , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/efectos adversosRESUMEN
R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor ß (TGF-ß), is reduced; that then leads to the activation of the TGF-ß pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins.
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Regulación de la Expresión Génica/genética , Regiones Promotoras Genéticas , ARN Helicasas/genética , ARN Helicasas/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , ADN/genética , ADN/ultraestructura , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN Helicasas , Metilación de ADN/genética , Humanos , Proteínas de la Membrana/metabolismo , Enzimas Multifuncionales , Mutación , Regiones Promotoras Genéticas/genética , Procesamiento Proteico-Postraduccional , ARN/genética , ARN/ultraestructura , Motivos de Unión al ARN , Activación Transcripcional/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Enhancers, critical regulatory elements within the human genome, are often transcribed into enhancer RNAs. The dysregulation of enhancers leads to diseases collectively termed enhanceropathies. While it is known that enhancers play a role in diseases by regulating gene expression, the specific mechanisms by which individual enhancers cause diseases are not well understood. Studies of individual enhancers are needed to fill this gap. This study delves into the role of APOE-activating noncoding RNA, AANCR, in the central nervous system, elucidating its function as a genetic modifier in Alzheimer's Disease. We employed RNA interference, RNaseH-mediated degradation, and single-molecule RNA fluorescence in situ hybridization to demonstrate that mere transcription of AANCR is insufficient; rather, its transcripts are crucial for promoting APOE expression. Our findings revealed that AANCR is induced by ATM-mediated ERK phosphorylation and subsequent AP-1 transcription factor activation. Once activated, AANCR enhances APOE expression, which in turn imparts an inflammatory phenotype to astrocytes. These findings demonstrate that AANCR is a key enhancer RNA in some cell types within the nervous system, pivotal for regulating APOE expression and influencing inflammatory responses, underscoring its potential as a therapeutic target in neurodegenerative diseases.
RESUMEN
Hereditary spastic paraplegia (HSP) comprises a large group of neurogenetic disorders characterized by progressive lower extremity spasticity. Neurological evaluation and genetic testing were completed in a Malian family with early-onset HSP. Three children with unaffected consanguineous parents presented with symptoms consistent with childhood-onset complicated HSP. Neurological evaluation found lower limb weakness, spasticity, dysarthria, seizures, and intellectual disability. Brain MRI showed corpus callosum thinning with cortical and spinal cord atrophy, and an EEG detected slow background in the index patient. Whole exome sequencing identified a homozygous missense variant in the adaptor protein (AP) complex 2 alpha-2 subunit (AP2A2) gene. Western blot analysis showed reduced levels of AP2A2 in patient-iPSC derived neuronal cells. Endocytosis of transferrin receptor (TfR) was decreased in patient-derived neurons. In addition, we observed increased axon initial segment length in patient-derived neurons. Xenopus tropicalis tadpoles with ap2a2 knockout showed cerebral edema and progressive seizures. Immunoprecipitation of the mutant human AP-2-appendage alpha-C construct showed defective binding to accessory proteins. We report AP2A2 as a novel genetic entity associated with HSP and provide functional data in patient-derived neuron cells and a frog model. These findings expand our understanding of the mechanism of HSP and improve the genetic diagnosis of this condition.
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Complejo 2 de Proteína Adaptadora , Endocitosis , Paraplejía Espástica Hereditaria , Animales , Niño , Preescolar , Femenino , Humanos , Masculino , Complejo 2 de Proteína Adaptadora/genética , Endocitosis/genética , Endocitosis/fisiología , Mutación/genética , Mutación Missense , Neuronas/metabolismo , Neuronas/patología , Linaje , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , XenopusRESUMEN
RNA is modified by hundreds of chemical reactions and folds into innumerable shapes. However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown. Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We found an enhancer RNA, AANCR, that regulates the transcription and expression of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified by N-glycosidic cleavage; in this form, AANCR is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in other cell types including hepatocytes and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. DNA sequence variants in AANCR are associated significantly with APOE expression and Alzheimer's Disease, thus AANCR is a modifier of Alzheimer's Disease. Besides AANCR, thousands of noncoding RNAs are regulated by abasic sites in R-loops. Together our data reveal the essentiality of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases such as Alzheimer's disease.
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Enfermedad de Alzheimer , Estructuras R-Loop , Humanos , ARN/genética , Enfermedad de Alzheimer/genética , Transcripción Genética , Apolipoproteínas E/genéticaRESUMEN
RNA abasic sites and the mechanisms involved in their regulation are mostly unknown; in contrast, DNA abasic sites are well-studied. We found surprisingly that, in yeast and human cells, RNA abasic sites are prevalent. When a base is lost from RNA, the remaining ribose is found as a closed-ring or an open-ring sugar with a reactive C1' aldehyde group. Using primary amine-based reagents that react with the aldehyde group, we uncovered evidence for abasic sites in nascent RNA, messenger RNA, and ribosomal RNA from yeast and human cells. Mass spectroscopic analysis confirmed the presence of RNA abasic sites. The RNA abasic sites were found to be coupled to R-loops. We show that human methylpurine DNA glycosylase cleaves N-glycosidic bonds on RNA and that human apurinic/apyrimidinic endonuclease 1 incises RNA abasic sites in RNA-DNA hybrids. Our results reveal that, in yeast and human cells, there are RNA abasic sites, and we identify a glycosylase that generates these sites and an AP endonuclease that processes them.
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Secuencia de Bases/genética , ARN/química , ARN/genética , Sitios de Unión , ADN/química , Daño del ADN/genética , ADN Glicosilasas/metabolismo , Reparación del ADN/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Desoxirribonucleasa I/metabolismo , Humanos , Nucleótidos/genética , Estructuras R-Loop/genética , Saccharomyces cerevisiae/genética , Especificidad por Sustrato , Levaduras/genéticaRESUMEN
Synaptojanin 2 binding protein (SYNJ2BP) is an outer mitochondrial membrane protein with a cytosolic PDZ domain that functions as a cellular signaling hub. Few studies have evaluated its role in disease. Here we use induced pluripotent stem cell (iPSC)-derived motor neurons and post-mortem tissue from patients with two hereditary motor neuron diseases, spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis type 4 (ALS4), and show that SYNJ2BP expression is increased in diseased motor neurons. Similarly, we show that SYNJ2BP expression increases in iPSC-derived motor neurons undergoing stress. Using proteomic analysis, we found that elevated SYNJ2BP alters the cellular distribution of mitochondria and increases mitochondrial-ER membrane contact sites. Furthermore, decreasing SYNJ2BP levels improves mitochondrial oxidative function in the diseased motor neurons. Together, our observations offer new insight into the molecular pathology of motor neuron disease and the role of SYNJ2BP in mitochondrial dysfunction.
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Esclerosis Amiotrófica Lateral , Enfermedad de la Neurona Motora , Atrofia Muscular Espinal , Esclerosis Amiotrófica Lateral/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Enfermedad de la Neurona Motora/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/patología , ProteómicaRESUMEN
Aberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes including MYO1E and SESN2, RNA Pol II pauses at precise nucleotide locations. Characterization of these sites shows that RNA Pol II pauses at GC-rich regions that are marked by a sequence motif. Sixty-five percent of the pause sites are cytosines. By differential allelic gene expression analysis, we showed in our samples and a population dataset from the Genotype-Tissue Expression (GTEx) consortium that genes with more paused polymerase have lower expression levels. Furthermore, mutagenesis of the pause sites led to a significant increase in promoter activities. Thus, our data uncover that RNA Pol II pauses precisely at sites with distinct sequence features that in turn regulate gene expression.
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Regulación de la Expresión Génica , ARN Polimerasa II/metabolismo , Adulto , Alelos , Células Cultivadas , Humanos , Recién NacidoRESUMEN
RNA/DNA hybrids form when RNA hybridizes with its template DNA generating a three-stranded structure known as the R-loop. Knowledge of how they form and resolve, as well as their functional roles, is limited. Here, by pull-down assays followed by mass spectrometry, we identified 803 proteins that bind to RNA/DNA hybrids. Because these proteins were identified using in vitro assays, we confirmed that they bind to R-loops in vivo. They include proteins that are involved in a variety of functions, including most steps of RNA processing. The proteins are enriched for K homology (KH) and helicase domains. Among them, more than 300 proteins preferred binding to hybrids than double-stranded DNA. These proteins serve as starting points for mechanistic studies to elucidate what RNA/DNA hybrids regulate and how they are regulated.
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Proteínas de Unión al ADN/química , ADN/química , Proteínas de Unión al ARN/química , ARN/química , Línea Celular , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Conformación de Ácido Nucleico , Unión Proteica , Dominios Proteicos , ARN/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
OBJECTIVE: To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. METHODS: Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. RESULTS: We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. INTERPRETATION: We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547-555.
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Esclerosis Amiotrófica Lateral/metabolismo , ADN Helicasas/metabolismo , Enzimas Multifuncionales/metabolismo , ARN Helicasas/metabolismo , Absorciometría de Fotón , Tejido Adiposo/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/fisiopatología , Western Blotting , Creatina Quinasa/metabolismo , Creatinina/metabolismo , ADN Helicasas/genética , Electromiografía , Femenino , Fibroblastos , Humanos , Células Madre Pluripotentes Inducidas , Lactante , Extremidad Inferior/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enzimas Multifuncionales/genética , Músculo Esquelético/diagnóstico por imagen , Mutación , Conducción Nerviosa , Estructuras R-Loop/genética , ARN Helicasas/genética , ARN Mensajero , Extremidad Superior/diagnóstico por imagen , Adulto JovenRESUMEN
BACKGROUND: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres. METHODS: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays. RESULTS: Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients. CONCLUSIONS: Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.
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Secuenciación del Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Mutación , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades Raras/diagnóstico , Adolescente , Adulto , Anciano , Enfermedades Genéticas Congénitas/genética , Humanos , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Enfermedades del Sistema Nervioso/genética , Linaje , Fenotipo , Enfermedades Raras/genética , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The aim of this study was to illustrate the current understanding and avenues for developing treatment in spinal and bulbar muscular atrophy (SBMA), an inherited neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor (AR) gene. RECENT FINDINGS: Important advances have been made in characterizing the molecular mechanism of the disease, including the disruption of protein homeostasis, intracellular trafficking and signalling pathways. Biomarkers such as MRI quantification of muscle volume and fat fraction have been used to track disease progression, and will be useful in future clinical studies. Therapies tested and under development have been based on diverse strategies, including targeting mutant AR gene expression, stability and activity, and pathways that mitigate disease toxicity. SUMMARY: We provide an overview of the recent advances in understanding the SBMA disease mechanism and highlight efforts to translate these insights into well tolerated and effective therapy.
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Atrofia Bulboespinal Ligada al X/genética , Receptores Androgénicos/genética , Expansión de Repetición de Trinucleótido , Biomarcadores , Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/terapia , Progresión de la Enfermedad , HumanosRESUMEN
RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.
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Calcio/metabolismo , Enfermedades Musculares/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Citoplasma/metabolismo , Humanos , Músculo Esquelético/metabolismo , Enfermedades Musculares/terapia , Canal Liberador de Calcio Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismoRESUMEN
Alterations of RNA sequences and structures, such as those from editing and alternative splicing, result in two or more RNA transcripts from a DNA template. It was thought that in yeast, RNA editing only occurs in tRNAs. Here, we found that Saccharomyces cerevisiae have all 12 types of RNA-DNA sequence differences (RDDs) in the mRNA. We showed these sequence differences are propagated to proteins, as we identified peptides encoded by the RNA sequences in addition to those by the DNA sequences at RDD sites. RDDs are significantly enriched at regions with R-loops. A screen of yeast mutants showed that RDD formation is affected by mutations in genes regulating R-loops. Loss-of-function mutations in ribonuclease H, senataxin, and topoisomerase I that resolve RNA-DNA hybrids lead to increases in RDD frequency. Our results demonstrate that RDD is a conserved process that diversifies transcriptomes and proteomes and provide a mechanistic link between R-loops and RDDs.
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Disparidad de Par Base , ADN de Hongos/genética , ARN de Hongos/genética , ARN Mensajero/genética , Saccharomyces cerevisiae/genética , ADN-Topoisomerasas de Tipo I/genética , ADN de Hongos/química , Mutación con Pérdida de Función , ARN de Hongos/química , ARN Mensajero/química , Ribonucleasa H/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders. Astrocyte-specific rescue of SMN protein levels has been shown to mitigate disease manifestations in mice. However, the mechanism by which SMN deficiency in astrocytes may contribute to SMA is unclear and what aspect of astrocyte activity is lacking is unknown. Therefore, it is worthwhile to identify defects in SMN-deficient astrocytes that compromise normal function. We show here that SMA astrocyte cultures derived from mouse spinal cord of both sexes are deficient in supporting both WT and SMN-deficient motor neurons derived from male, female, and mixed-sex sources and that this deficiency may be mitigated with secreted factors. In particular, SMN-deficient astrocytes have decreased levels of monocyte chemoactive protein 1 (MCP1) secretion compared with controls and MCP1 restoration stimulates outgrowth of neurites from cultured motor neurons. Correction of MCP1 deficiency may thus be a new therapeutic approach to SMA.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is caused by the loss of motor neurons, but astrocyte dysfunction also contributes to the disease in mouse models. Monocyte chemoactive protein 1 (MCP1) has been shown to be neuroprotective and is released by astrocytes. Here, we report that MCP1 levels are decreased in SMA mice and that replacement of deficient MCP1 increases differentiation and neurite length of WT and SMN-deficient motor-neuron-like cells in cell culture. This study reveals a novel aspect of astrocyte dysfunction in SMA and indicates a possible approach for improving motor neuron growth and survival in this disease.
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Astrocitos/metabolismo , Quimiocina CCL2/metabolismo , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Animales , Astrocitos/citología , Células Cultivadas , Quimiocina CCL2/genética , Femenino , Humanos , Masculino , Ratones , Neuronas Motoras/citología , Médula Espinal/citología , Médula Espinal/metabolismo , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismoRESUMEN
Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.
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Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Neuronas Motoras/patología , Degeneración Nerviosa/genética , ARN Helicasas/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , ADN Helicasas , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Ratones , Neuronas Motoras/metabolismo , Enzimas Multifuncionales , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Fenotipo , ARN Helicasas/metabolismoRESUMEN
Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is an X-linked neuromuscular condition clinically characterised by weakness, atrophy and fasciculations of the limb and bulbar muscles, as a result of lower motor neuron degeneration. The disease is caused by an abnormally expanded triplet repeat expansions in the ubiquitously expressed androgen receptor gene, through mechanisms which are not entirely elucidated. Over the years studies from both humans and animal models have highlighted the involvement of cell populations other than motor neurons in SBMA, widening the disease phenotype. The most compelling aspect of these findings is their potential for therapeutic impact: muscle, for example, which is primarily affected in the disease, has been recently shown to represent a valid alternative target for therapy to motor neurons. In this review, we discuss the emerging study of the extra-motor neuron involvement in SBMA, which, besides increasingly pointing towards a multidisciplinary approach for affected patients, deepens our understanding of the pathogenic mechanisms and holds potential for providing new therapeutic targets for this disease.
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Enfermedades del Sistema Nervioso Autónomo/patología , Atrofia Bulboespinal Ligada al X/patología , Neuronas Motoras/patología , Atrofia Muscular/patología , Obstrucción del Cuello de la Vejiga Urinaria/patología , Enfermedades del Sistema Nervioso Autónomo/genética , Atrofia Bulboespinal Ligada al X/genética , Humanos , Atrofia Muscular/genética , Fenotipo , Expansión de Repetición de Trinucleótido , Obstrucción del Cuello de la Vejiga Urinaria/genéticaRESUMEN
INTRODUCTION: The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. This study describes symptoms from the patient's perspective and the impact these symptoms have on QoL. METHODS: We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes. RESULTS: From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. DISCUSSION: Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials. Muscle Nerve 57: 40-44, 2018.
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Trastornos Musculares Atróficos/psicología , Adulto , Anciano , Actitud , Emociones , Femenino , Humanos , Entrevista Psicológica , Masculino , Salud Mental , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Debilidad Muscular/psicología , Trastornos Musculares Atróficos/fisiopatología , Calidad de VidaRESUMEN
INTRODUCTION: This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). METHODS: We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. RESULTS: All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients. DISCUSSION: A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.