RESUMEN
Voltage-gated Ca2+ (CaV ) channels are crucial for neuronal excitability and synaptic transmission upon depolarization. Their properties in vivo are modulated by their interaction with a variety of scaffolding proteins. Such interactions can influence the function and localization of CaV channels, as well as their coupling to intracellular second messengers and regulatory pathways, thus amplifying their signaling potential. Among these scaffolding proteins, a subset of PDZ (postsynaptic density-95, Drosophila discs-large, and zona occludens)-domain containing proteins play diverse roles in modulating CaV channel properties. At the presynaptic terminal, PDZ proteins enrich CaV channels in the active zone, enabling neurotransmitter release by maintaining a tight and vital link between channels and vesicles. In the postsynaptic density, these interactions are essential in regulating dendritic spine morphology and postsynaptic signaling cascades. In this review, we highlight the studies that demonstrate dynamic regulations of neuronal CaV channels by PDZ proteins. We discuss the role of PDZ proteins in controlling channel activity, regulating channel cell surface density, and influencing channel-mediated downstream signaling events. We highlight the importance of PDZ protein regulations of CaV channels and evaluate the link between this regulatory effect and human disease.
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Canales de Calcio/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Neuronas/metabolismo , Transmisión Sináptica/fisiología , Animales , HumanosRESUMEN
Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7â¯years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal & bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.
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Autofagia/fisiología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/terapia , Animales , HumanosRESUMEN
Spinal and Bulbar Muscular Atrophy (SBMA) is an inherited neuromuscular disorder caused by a CAG-polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene. Unlike other polyQ diseases, where the function of the native causative protein is unknown, the biology of AR is well understood, and this knowledge has informed our understanding of how native AR function interfaces with polyQ-AR dysfunction. Furthermore, ligand-dependent activation of AR has been linked to SBMA disease pathogenesis, and has led to a thorough study of androgen-mediated effects on polyQ-AR stability, degradation, and post-translational modifications, as well as their roles in the disease process. Transcriptional dysregulation, proteostasis dysfunction, and mitochondrial abnormalities are central to polyQ-AR neurotoxicity, most likely via a 'change-of-function' mechanism. Intriguingly, recent work has demonstrated a principal role for skeletal muscle in SBMA disease pathogenesis, indicating that polyQ-AR toxicity initiates in skeletal muscle and results in secondary motor neuron demise. The existence of robust animal models for SBMA has permitted a variety of preclinical trials, driven by recent discoveries of altered cellular processes, and some of this preclinical work has led to human clinical trials. In this chapter, we review SBMA clinical features and disease biology, discuss our current understanding of the cellular and molecular basis of SBMA pathogenesis, and highlight ongoing efforts toward therapy development.
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Atrofia Bulboespinal Ligada al X , Mitocondrias , Neuronas Motoras , Músculo Esquelético , Péptidos , Deficiencias en la Proteostasis , Expansión de Repetición de Trinucleótido , Animales , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Péptidos/genética , Péptidos/metabolismo , Deficiencias en la Proteostasis/genética , Deficiencias en la Proteostasis/metabolismo , Deficiencias en la Proteostasis/patología , Ratas , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transcripción Genética/genéticaRESUMEN
Autophagy is an essential, fundamentally important catabolic pathway in which double membrane-bound vesicles form in the cytosol and encircle macromolecules and organelles to permit their degradation after fusion with lysosomes. More than a decade of research has revealed that autophagy is required for normal central nervous system (CNS) function and plays a central role in maintaining protein and organelle quality controls in neurons. Neurodegenerative diseases occur when misfolded proteins accumulate and disrupt normal cellular processes, and autophagy has emerged as a key arbiter of the cell's homeostatic response to this threat. One class of inherited neurodegenerative disease is known as the CAG/polyglutamine repeat disorders, and these diseases all result from the expansion of a CAG repeat tract in the coding regions of distinct genes. Polyglutamine (polyQ) repeat diseases result in the production polyQ-expanded proteins that misfold to form inclusions or aggregates that challenge the main cellular proteostasis system of the cell, the ubiquitin proteasome system (UPS). The UPS cannot efficiently degrade polyQ-expanded disease proteins, and components of the UPS are enriched in polyQ disease aggregate bodies found in degenerating neurons. In addition to components of the UPS, polyQ protein cytosolic aggregates co-localize with key autophagy proteins, even in autophagy deficient cells, suggesting that they probably do not reflect the formation of autophagosomes but rather the sequestration of key autophagy components. Furthermore, recent evidence now implicates polyQ proteins in the regulation of the autophagy pathway itself. Thus, a complex model emerges where polyQ proteins play a dual role as both autophagy substrates and autophagy offenders. In this review, we consider the role of autophagy in polyQ disorders and the therapeutic potential for autophagy modulation in these diseases. This article is part of a Special Issue entitled "Neuronal Protein".
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Autofagia/fisiología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/fisiopatología , Péptidos/genética , Animales , Humanos , Modelos Biológicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Pliegue de ProteínaRESUMEN
Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-ß plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cell-cell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.
RESUMEN
Autophagy is a cell survival response to nutrient deprivation that delivers cellular components to lysosomes for digestion. In recent years, autophagy has also been shown to assist in the degradation of misfolded proteins linked to neurodegenerative disease (Ross and Poirier, 2004). In support of this, rapamycin, an autophagy inducer, improves the phenotype of several animal models of neurodegenerative disease. Our Tg(PrP-A116V) mice model Gerstmann-Sträussler-Scheinker disease (GSS), a genetic prion disease characterized by prominent ataxia and extracellular PrP amyloid plaque deposits in brain (Yang et al., 2009). To determine whether autophagy induction can mitigate the development of GSS, Tg(PrP-A116V) mice were chronically treated with 10 or 20 mg/kg rapamycin intraperitoneally thrice weekly, beginning at 6 weeks of age. We observed a dose-related delay in disease onset, a reduction in symptom severity, and an extension of survival in rapamycin-treated Tg(PrP-A116V) mice. Coincident with this response was an increase in the autophagy-specific marker LC3II, a reduction in insoluble PrP-A116V, and a near-complete absence of PrP amyloid plaques in the brain. An increase in glial cell apoptosis of unclear significance was also detected. These findings suggest autophagy induction enhances elimination of misfolded PrP before its accumulation in plaques. Because ataxia persisted in these mice despite the absence of plaque deposits, our findings also suggest that PrP plaque pathology, a histopathological marker for the diagnosis of GSS, is not essential for the GSS phenotype.
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Modelos Animales de Enfermedad , Enfermedad de Gerstmann-Straussler-Scheinker/prevención & control , Placa Amiloide/prevención & control , Priones/antagonistas & inhibidores , Sirolimus/uso terapéutico , Animales , Femenino , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Priones/metabolismo , Distribución Aleatoria , Factores de TiempoRESUMEN
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally.
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Atrofia Bulboespinal Ligada al X , Ratones , Humanos , Masculino , Animales , Anciano , Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/patología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Neuronas Motoras/metabolismo , Ratones Transgénicos , Fenotipo , Degeneración Nerviosa/patologíaRESUMEN
Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
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Enfermedades Neurodegenerativas , Ratones , Animales , Factores de Transcripción , Enfermedades Neuroinflamatorias , Músculo Esquelético , Ratones Transgénicos , Envejecimiento , Sistema Nervioso Central , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-HéliceRESUMEN
Physical activity is a powerful lifestyle factor capable of improving cognitive function, modifying the risk for dementia associated with neurodegeneration and possibly slowing neurodegenerative disease progression in both men and women. However, men and women show differences in the biological responses to physical activity and in the vulnerabilities to the onset, progression and outcome of neurodegenerative diseases, prompting the question of whether sex-specific regulatory mechanisms might differentially modulate the benefits of exercise on the brain. Mechanistic studies aimed to better understand how physical activity improves brain health and function suggest that the brain responds to physical exercise by overall reducing neuroinflammation and increasing neuroplasticity. Here, we review the emerging literature considering sex-specific differences in the immune system response to exercise as a potential mechanism by which physical activity affects the brain. Although the literature addressing sex differences in this light is limited, the initial findings suggest a potential influence of biological sex in the brain benefits of exercise, and lay out a scientific foundation to support very much needed studies investigating the potential effects of sex-differences on exercise neurobiology. Considering biological sex and sex-differences in the neurobiological hallmarks of exercise will help to enhance our understanding of the mechanisms by which physical activity benefits the brain and also improve the development of treatments and interventions for diseases of the central nervous system.
RESUMEN
Regular exercise plays an essential role in maintaining healthy neurocognitive function and central nervous system (CNS) immuno-metabolism in the aging CNS. Physical activity decreases the risk of developing Alzheimer's Disease (AD), is associated with better AD prognosis, and positively affects cognitive function in AD patients. Skeletal muscle is an important secretory organ, communicating proteotoxic and metabolic stress to distant tissues, including the CNS, through the secretion of bioactive molecules collectively known as myokines. Skeletal muscle undergoes significant physical and metabolic remodeling during exercise, including alterations in myokine expression profiles. This suggests that changes in myokine and myometabolite secretion may underlie the well-documented benefits of exercise in AD. However, to date, very few studies have focused on specific alterations in skeletal muscle-originating secreted factors and their potential neuroprotective effects in AD. In this review, we discuss exercise therapy for AD prevention and intervention, and propose the use of circulating myokines as novel therapeutic tools for modifying AD progression.
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Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity.
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Atrofia Bulboespinal Ligada al X , Receptores Androgénicos , Animales , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/terapia , Terapia Genética , Ratones , Fenotipo , Isoformas de Proteínas/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Measurement of animal locomotion is a common behavioral tool used to describe the phenotype of a given disease, injury, or drug model. The low-cost method of gait analysis demonstrated here is a simple but effective measure of gait abnormalities in murine models. Footprints are analyzed by painting a mouse's feet with non-toxic washable paint and allowing the subject to walk through a tunnel on a sheet of paper. The design of the testing tunnel takes advantage of natural mouse behavior and their affinity for small dark places. The stride length, stride width, and toe spread of each mouse is easily measured using a ruler and a pencil. This is a well-established and reliable method, and it generates several metrics that are analogous to digital systems. This approach is sensitive enough to detect changes in stride early in phenotype presentation, and due to its non-invasive approach, it allows for testing of groups across life-span or phenotypic presentation.
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Conducta Animal , Costos y Análisis de Costo , Análisis de la Marcha/métodos , Enfermedades Neuromusculares/fisiopatología , Fenotipo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , CaminataRESUMEN
Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.
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Modelos Animales de Enfermedad , Inmunidad Mucosa/inmunología , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/patología , Cicatrización de Heridas , Animales , Humanos , Enfermedades Inflamatorias del Intestino/etiologíaRESUMEN
AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.
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Autofagia/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Lisosomas/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores Androgénicos/metabolismo , Transcripción Genética , Andrógenos/farmacología , Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Metástasis de la Neoplasia , Pronóstico , Transcripción Genética/efectos de los fármacosRESUMEN
The scope of the present study was to evaluate the presence and activation of proacrosin/acrosin as a tool to determine the acrosomal status of fresh and frozen/thawed dog spermatozoa. Monoclonal antibody C5F11, directed against human acrosin, cross-reacted with dog spermatozoa and labeled the acrosome of both fresh and frozen/thawed dog spermatozoa. Frozen/thawed spermatozoa had a lesser proportion of labeled spermatozoa than fresh spermatozoa (P<0.05). When live spermatozoa were labeled with soybean trypsin inhibitor conjugated with Alexa 488 (SBTI-Alexa 488), the proportion of acrosome-labeled fresh spermatozoa was less than frozen/thawed spermatozoa (P<0.05). By using Western blots and enzymatic activity, frozen/thawed spermatozoa had a greater proportion of active acrosin than fresh spermatozoa. In addition, beta 1,4-galactosyl-transferase (GalT), a plasma membrane bound protein, remained attached to frozen/thawed spermatozoa. Proacrosin is activated during freezing/thawing of dog spermatozoa, and that proacrosin/acrosin may be a good indicator of acrosomal integrity of frozen/thawed spermatozoa.
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Acrosina/inmunología , Acrosoma , Anticuerpos Monoclonales/inmunología , Perros/fisiología , Precursores Enzimáticos/inmunología , Espermatozoides/fisiología , Acrosina/metabolismo , Acrosoma/inmunología , Acrosoma/fisiología , Reacción Acrosómica/fisiología , Animales , Western Blotting/veterinaria , Precursores Enzimáticos/metabolismo , Masculino , Preservación de Semen/veterinaria , Espermatozoides/enzimología , Espermatozoides/inmunologíaRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.
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Proteínas Quinasas Activadas por Mitógenos/metabolismo , Trastornos Musculares Atróficos/patología , Receptores Androgénicos/metabolismo , Animales , Línea Celular , Drosophila , Histocitoquímica , Humanos , Ratones , Músculos/patología , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas , Médula Espinal/patología , Análisis de SupervivenciaRESUMEN
Non-cell autonomous degeneration has arisen as an important mechanism in neurodegenerative disorders. Using a novel line of BAC androgen receptor (AR) transgenic mice with a floxed transgene (BAC fxAR121), we uncovered a key role for skeletal muscle in X-linked Spinal and Bulbar Muscular Atrophy (SBMA), a motor neuronopathy caused by a polyglutamine expansion in exon 1 of the AR gene. By excising the mutant AR transgene from muscle only, we achieved complete rescue of neuromuscular phenotypes in these mice, despite retaining strong CNS expression. Furthermore, we delivered an antisense oligonucleotide (ASO) directed against the human AR transgene by peripheral injection, and documented that peripheral ASO delivery could rescue muscle weakness and premature death in BAC fxAR121 mice. Our results reveal a crucial role for skeletal muscle in SBMA disease pathogenesis, and offer an appealing avenue for therapy development for SBMA and perhaps also for related motor neuron diseases.