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1.
Acta Neuropathol ; 143(6): 713-731, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35522298

RESUMEN

Androgens and androgen-related molecules exert a plethora of functions across different tissues, mainly through binding to the transcription factor androgen receptor (AR). Despite widespread therapeutic use and misuse of androgens as potent anabolic agents, the molecular mechanisms of this effect on skeletal muscle are currently unknown. Muscle mass in adulthood is mainly regulated by the bone morphogenetic protein (BMP) axis of the transforming growth factor (TGF)-ß pathway via recruitment of mothers against decapentaplegic homolog 4 (SMAD4) protein. Here we show that, upon activation, AR forms a transcriptional complex with SMAD4 to orchestrate a muscle hypertrophy programme by modulating SMAD4 chromatin binding dynamics and enhancing its transactivation activity. We challenged this mechanism of action using spinal and bulbar muscular atrophy (SBMA) as a model of study. This adult-onset neuromuscular disease is caused by a polyglutamine expansion (polyQ) in AR and is characterized by progressive muscle weakness and atrophy secondary to a combination of lower motor neuron degeneration and primary muscle atrophy. Here we found that the presence of an elongated polyQ tract impairs AR cooperativity with SMAD4, leading to an inability to mount an effective anti-atrophy gene expression programme in skeletal muscle in response to denervation. Furthermore, adeno-associated virus, serotype 9 (AAV9)-mediated muscle-restricted delivery of BMP7 is able to rescue the muscle atrophy in SBMA mice, supporting the development of treatments able to fine-tune AR-SMAD4 transcriptional cooperativity as a promising target for SBMA and other conditions associated with muscle loss.


Asunto(s)
Atrofia Muscular Espinal , Receptores Androgénicos , Andrógenos/metabolismo , Andrógenos/farmacología , Animales , Homeostasis , Ratones , Ratones Transgénicos , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Receptores Androgénicos/genética , Proteína Smad4
2.
J Neurosci ; 40(4): 932-941, 2020 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-31811028

RESUMEN

Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.


Asunto(s)
Predisposición Genética a la Enfermedad , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Receptores de Dopamina D2/genética , Receptores de Estrógenos/genética , Esquizofrenia/genética , Animales , Simulación por Computador , Redes Reguladoras de Genes , Humanos , Ratones , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Regiones Promotoras Genéticas , Receptor Relacionado con Estrógeno ERRalfa
3.
Pflugers Arch ; 473(8): 1213-1227, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34021780

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansions in the androgen receptor (AR) gene. SBMA is characterized by selective dysfunction and degeneration of motor neurons in the brainstem and spinal cord through still unclear mechanisms in which ion channel modulation might play a central role as for other neurodegenerative diseases. The beta2-adrenergic agonist clenbuterol was observed to ameliorate the SBMA phenotype in mice and patient-derived myotubes. However, the underlying molecular mechanism has yet to be clarified. Here, we unveil that ionic current alterations induced by the expression of polyQ-expanded AR in motor neuron-derived MN-1 cells are attenuated by the administration of clenbuterol. Our combined electrophysiological and pharmacological approach allowed us to reveal that clenbuterol modifies delayed outward potassium currents. Overall, we demonstrated that the protection provided by clenbuterol restores the normal function through the modulation of KV2-type outward potassium currents, possibly contributing to the protective effect on motor neuron toxicity in SBMA.


Asunto(s)
Atrofia Bulboespinal Ligada al X/etiología , Canales de Potasio de Tipo Rectificador Tardío/metabolismo , Animales , Proteínas de Artrópodos , Atrofia Bulboespinal Ligada al X/metabolismo , Línea Celular , Clenbuterol , Humanos , Ratones , Técnicas de Placa-Clamp , Venenos de Araña
4.
Front Neuroendocrinol ; 57: 100821, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32006533

RESUMEN

The pleiotropic peptide insulin-like growth factor 1 (IGF-I) regulates human body homeostasis and cell growth. IGF-I activates two major signaling pathways, namely phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt) and Ras/extracellular signal-regulated kinase (ERK), which contribute to brain development, metabolism and function as well as to neuronal maintenance and survival. In this review, we discuss the general and tissue-specific effects of the IGF-I pathways. In addition, we present a comprehensive overview examining the role of IGF-I in neurodegenerative diseases, such as spinal and muscular atrophy, amyotrophic lateral sclerosis, and polyglutamine diseases. In each disease, we analyze the disturbances of the IGF-I pathway, the modification of the disease protein by IGF-I signaling, and the therapeutic strategies based on the use of IGF-I developed to date. Lastly, we highlight present and future considerations in the use of IGF-I for the treatment of these disorders.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/fisiología , Neuronas Motoras/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Péptidos , Transducción de Señal/fisiología , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Glutamina/genética , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Sistema de Señalización de MAP Quinasas/fisiología , Atrofia Muscular Espinal/fisiopatología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas ras/metabolismo
5.
Neurobiol Dis ; 140: 104849, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32222473

RESUMEN

Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-ß 1-42 (Aß 1-42). The downstream effects of Aß 1-42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent Aß-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of Aß-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Muerte Celular/fisiología , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Transglutaminasas/metabolismo , Precursor de Proteína beta-Amiloide , Animales , Modelos Animales de Enfermedad , Hipocampo , Ratones
6.
Acta Neuropathol ; 140(1): 63-80, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32306066

RESUMEN

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.


Asunto(s)
Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/patología , Factores de Transcripción MEF2/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Animales , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Péptidos
7.
J Neurol Neurosurg Psychiatry ; 91(10): 1085-1091, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32934110

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.


Asunto(s)
Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/terapia , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Tejido Adiposo/diagnóstico por imagen , Agonistas Adrenérgicos beta/uso terapéutico , Autofagia , Biomarcadores , Atrofia Bulboespinal Ligada al X/diagnóstico por imagen , Atrofia Bulboespinal Ligada al X/fisiopatología , Clenbuterol/uso terapéutico , Creatinina/metabolismo , Dutasterida/uso terapéutico , Glucólisis , Humanos , Factor I del Crecimiento Similar a la Insulina/análogos & derivados , Leuprolida/uso terapéutico , Imagen por Resonancia Magnética , Mitocondrias/metabolismo , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Oligonucleótidos Antisentido/uso terapéutico , Oxidación-Reducción , Tratamiento con ARN de Interferencia , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Expansión de Repetición de Trinucleótido
8.
Hum Mol Genet ; 26(6): 1087-1103, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28087734

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared with glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in nicotinamide adenine dinucleotide-stained muscle cross-sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches toward improving the mitochondrial network are worth considering to support SBMA patients.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Trastornos Musculares Atróficos/genética , Péptidos/genética , Receptores Androgénicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/fisiopatología , Andrógenos/metabolismo , Animales , Biopsia , ADN Mitocondrial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitofagia/genética , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Trastornos Musculares Atróficos/fisiopatología
9.
Hum Mol Genet ; 26(19): 3749-3762, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28934387

RESUMEN

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6. To gain insights into the molecular basis of mutant TG6-induced neurotoxicity, we analyzed all the seven new TG6 mutants and the five TG6 mutants previously linked to SCA35. We found that the wild-type (TG6-WT) protein mainly localized to the nucleus and perinuclear area, whereas five TG6 mutations showed nuclear depletion, increased accumulation in the perinuclear area, insolubility and loss of enzymatic function. Aberrant accumulation of these TG6 mutants in the perinuclear area led to activation of the unfolded protein response (UPR), suggesting that specific TG6 mutants elicit an endoplasmic reticulum stress response. Mutations associated with activation of the UPR caused death of primary neurons and reduced the survival of novel Drosophila melanogaster models of SCA35. These results indicate that mutations differently impacting on TG6 function cause neuronal dysfunction and death through diverse mechanisms and highlight the UPR as a potential therapeutic target for patient treatment.


Asunto(s)
Ataxias Espinocerebelosas/genética , Transglutaminasas/genética , Transglutaminasas/metabolismo , Respuesta de Proteína Desplegada/genética , Animales , Animales Modificados Genéticamente , Células COS , Línea Celular , Chlorocebus aethiops , Drosophila melanogaster , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/genética , Femenino , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Mutación , Neuronas/enzimología , Neuronas/metabolismo , Neuronas/patología , Ataxias Espinocerebelosas/enzimología , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patología
10.
J Neurol Neurosurg Psychiatry ; 89(8): 808-812, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29353237

RESUMEN

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.


Asunto(s)
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/genética
11.
Acta Neuropathol ; 132(1): 127-44, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26971100

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Glucólisis , Músculo Esquelético/metabolismo , Trastornos Musculares Atróficos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Atrofia/metabolismo , Atrofia/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Glucólisis/fisiología , Humanos , Metabolismo de los Lípidos/fisiología , Masculino , Potencial de la Membrana Mitocondrial/fisiología , Ratones Transgénicos , Músculo Esquelético/patología , Trastornos Musculares Atróficos/patología , Oxidación-Reducción , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Distribución Aleatoria , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal
12.
J Neurol Neurosurg Psychiatry ; 87(8): 810-6, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26503015

RESUMEN

OBJECTIVE: To carry out a deep characterisation of the main androgen-responsive tissues involved in spinal and bulbar muscular atrophy (SBMA). METHODS: 73 consecutive Italian patients underwent a full clinical protocol including biochemical and hormonal analyses, genitourinary examination, bone metabolism and densitometry, cardiological evaluation and muscle pathology. RESULTS: Creatine kinase levels were slightly to markedly elevated in almost all cases (68 of the 73; 94%). 30 (41%) patients had fasting glucose above the reference limit, and many patients had total cholesterol (40; 54.7%), low-density lipoproteins cholesterol (29; 39.7%) and triglyceride (35; 48%) levels above the recommended values. Although testosterone, luteinising hormone and follicle-stimulating hormone values were generally normal, in one-third of cases we calculated an increased Androgen Sensitivity Index reflecting the presence of androgen resistance in these patients. According to the International Prostate Symptom Score (IPSS), 7/70 (10%) patients reported severe lower urinal tract symptoms (IPSS score >19), and 21/73 (30%) patients were moderately symptomatic (IPSS score from 8 to 19). In addition, 3 patients were carriers of an indwelling bladder catheter. Videourodynamic evaluation indicated that 4 of the 7 patients reporting severe urinary symptoms had an overt prostate-unrelated bladder outlet obstruction. Dual-energy X-ray absorptiometry scan data were consistent with low bone mass in 25/61 (41%) patients. Low bone mass was more frequent at the femoral than at the lumbar level. Skeletal muscle biopsy was carried out in 20 patients and myogenic changes in addition to the neurogenic atrophy were mostly observed. CONCLUSIONS: Our study provides evidence of a wide non-neural clinical phenotype in SBMA, suggesting the need for comprehensive multidisciplinary protocols for these patients.


Asunto(s)
Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatología , Adulto , Anciano , Síndrome de Resistencia Androgénica/complicaciones , Glucemia/metabolismo , Densidad Ósea , Estudios de Casos y Controles , Creatina Quinasa/sangre , Humanos , Italia , Lípidos/sangre , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/patología , Fenotipo , Enfermedades Urológicas/complicaciones
13.
Stem Cell Res ; 81: 103544, 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39260069

RESUMEN

Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder with a birth incidence of 1:25,000. SMS is caused by haploinsufficiency of the retinoic acid-induced retinoic acid1 (RAI1) gene, determined by an interstitial deletion of âˆ¼ 3.7 Mb (17p11.2, including the RAI1 gene) in 90 % of cases and a mutation on the RAI1 gene in only 10 % of cases. We generated and characterized a human pluripotent stem cell line (hIPSCs) derived from primary fibroblasts of a 17-year-old woman carrying a 17p11.2 deletion including the RAI1 gene.

14.
Stem Cell Res ; 78: 103468, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38852424

RESUMEN

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A.


Asunto(s)
Células Madre Pluripotentes Inducidas , ARN Polimerasa III , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , ARN Polimerasa III/genética , ARN Polimerasa III/metabolismo , Línea Celular , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Masculino , Alelos
15.
Acta Neuropathol ; 126(1): 109-21, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23644820

RESUMEN

Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis.


Asunto(s)
Andrógenos/farmacología , Dihidrotestosterona/farmacología , Desarrollo de Músculos/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Interacciones Farmacológicas , Femenino , Humanos , Hipertrofia/inducido químicamente , Etiquetado Corte-Fin in Situ , Interleucina-4/farmacología , Interleucina-4/fisiología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Miosinas/metabolismo , Péptidos/genética , Factores de Tiempo , Adulto Joven
16.
Brain ; 135(Pt 7): 2032-47, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22689911

RESUMEN

Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations.


Asunto(s)
Diferenciación Celular/fisiología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Modelos Animales de Enfermedad , Proteína P0 de la Mielina/fisiología , Células de Schwann/citología , Células de Schwann/metabolismo , Potenciales de Acción/fisiología , Animales , Axones/patología , Axones/fisiología , Axones/ultraestructura , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Retículo Endoplásmico/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Técnicas de Sustitución del Gen/métodos , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación , Proteína P0 de la Mielina/genética , Vaina de Mielina/genética , Vaina de Mielina/patología , Conducción Nerviosa/fisiología , Proteínas Proto-Oncogénicas c-jun/biosíntesis , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Células de Schwann/ultraestructura , Nervio Ciático/patología , Nervio Ciático/fisiopatología , Nervio Ciático/ultraestructura , Factor de Transcripción CHOP/metabolismo , Respuesta de Proteína Desplegada/fisiología
17.
Cells ; 12(3)2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36766844

RESUMEN

Skeletal muscle is the most abundant tissue in the body and requires high levels of energy to function properly. Skeletal muscle allows voluntary movement and body posture, which require different types of fiber, innervation, energy, and metabolism. Here, we summarize the contribution received at the time of publication of this Introductory Issue for the Special Issue dedicated to "Skeletal Muscle Atrophy: Mechanisms at a Cellular Level". The Special Issue is divided into three sections. The first is dedicated to skeletal muscle pathophysiology, the second to disease mechanisms, and the third to therapeutic development.


Asunto(s)
Músculo Esquelético , Atrofia Muscular , Humanos , Atrofia Muscular/patología , Músculo Esquelético/metabolismo
18.
Curr Opin Pharmacol ; 71: 102394, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37463556

RESUMEN

The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years later by Dr. W. Kennedy. SBMA is a neuromuscular disease caused by expansions of a CAG microsatellite tandem repeat in exon 1 of the androgen receptor (AR) gene located on the X chromosome. These expansions result in the production of AR with an aberrantly expanded polyglutamine (polyQ) tract. In this review, we explore recent advancements in the significance of gene expression changes in skeletal muscle and discuss how pharmacological interventions targeting this aspect of disease pathogenesis can potentially be translated into therapies for SBMA patients.


Asunto(s)
Atrofia Bulboespinal Ligada al X , Humanos , Atrofia Bulboespinal Ligada al X/tratamiento farmacológico , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/uso terapéutico , Músculo Esquelético/metabolismo , Atrofia Muscular
19.
Sci Rep ; 13(1): 17311, 2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37828349

RESUMEN

Serum creatinine has been indicated as a potential marker of motor function in SBMA and results form previous longitudinal studies pointed to its decline over time. This is a longitudinal retrospective study investigating creatinine changes over a 36-month-period in 73 patients with SBMA. Severity and progression of the disease was assessed according to serum creatine kinase (CK) values, manual muscle testing (MMT), SBMA functional rating scale (SBMAFRS) score, 6-min-walk test (6MWT) value, and spirometry (forced vital capacity, fVC%) obtained at the baseline and at each of the annual follow-up visits. Baseline serum creatinine concentrations positively correlated with 6MWT, the MMT megascore score of both the upper (ULM) and lower (LLM) limbs and SBMAFRS. No correlation was found with CK or fVC% values. Similar correlation results were achieved at all the subsequent time points. Longitudinal assessments conducted by the generalized estimating equations (GEE) method returned significant changes for SBMAFRS (- 1.41 points per year, p < 0.001), ULM and LLM (- 0.69, p = 0.01; and - 1.07, p < 0.001, respectively), 6MWT (- 47 m, p < 0.001) but not for creatinine (- 0.82, p > 0.05). We also observed that creatinine levels at baseline did not correlate with changes in the other measures from baseline at each annual visit. Our data do not support a role for serum creatinine as sensitive biomarker of disease progression, and possibily prognosis, in SBMA.


Asunto(s)
Atrofia Bulboespinal Ligada al X , Atrofia Muscular Espinal , Humanos , Creatinina , Estudios Retrospectivos , Biomarcadores , Progresión de la Enfermedad
20.
J Clin Endocrinol Metab ; 108(5): 1181-1191, 2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-36394509

RESUMEN

CONTEXT: Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. OBJECTIVE: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. METHODS: A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. RESULTS: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. CONCLUSION: This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.


Asunto(s)
Infertilidad Masculina , Oligospermia , Humanos , Masculino , Oligospermia/genética , Receptores Androgénicos/genética , Hormona Folículo Estimulante/genética , Andrógenos , Semen , Infertilidad Masculina/epidemiología , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Mutación
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