Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the “97Q” model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the “myogenic” model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.

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Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy

PLoS ONE ◽

10.1371/journal.pone.0012922 ◽

2010 ◽

Vol 5 (9) ◽

pp. e12922 ◽

Cited By ~ 37

Author(s):

Kaiguo Mo ◽

Zak Razak ◽

Pengcheng Rao ◽

Zhigang Yu ◽

Hiroaki Adachi ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Mouse Models ◽

Microarray Analysis ◽

Muscular Atrophy ◽

Spinal Bulbar Muscular Atrophy

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Assessment of motor neuron pathology and potential compensatory mechanisms in phenotypically normal mice with reduced Survival Motor Neuron levels.

Journal of Student Science and Technology ◽

10.13034/jsst.v8i1.42 ◽

2015 ◽

Vol 8 (1) ◽

Author(s):

Rebecca Xu Xu ◽

Lyndsay M. Murray M. Murray Murray ◽

Yves De Repentigny De Repentigny ◽

Rashmi Kothary Kothary

Keyword(s):

Motor Neuron ◽

Mouse Models ◽

Motor Neurons ◽

Neuromuscular Junctions ◽

Muscular Atrophy ◽

Neuromuscular Disorder ◽

Survival Motor Neuron ◽

Compensatory Mechanisms ◽

Protein Levels ◽

Smn Protein

Spinal muscular atrophy (SMA) is a destructive pediatric neuromuscular disorder caused by low survival motor neuron (Smn) protein levels due to mutations and deletions within the survival motor neuron 1 (SMN1) gene. Motor neurons are the main pathological targets, and along with neuromuscular junctions (NMJs), they play an early significant role in the pathogenesis of SMA. Previous studies demonstrate that a pathological reduction in Smn levels can lead to significant remodeling defects in both the outgrowth of axonal sprouts and in the nerve-directed clustering of AChRs in mouse models. However, whether this pathological reduction in Smn leads to ubclinical features has not been investigated. Here, we have employed the Smn2B/2B and Smn+/- mouse models to study whether similar SMA pathology is present sub-clinically, and if so whether there is any compensation present. We show a decrease in the motor neuron number in the mouse models, no change in myelin thickness and modest NMJ pathology in both mouse models. Additionally, compensation through the expansion of the motor unit size is suggested.L’amyotrophie spinale (AMS) est un trouble neuromusculaire pédiatrique destructif causé par le niveau bas de protéine du neurone de moteur de survie (NMS) en raison des mutations et des effacements dans le neurone de moteur de survie 1 gène (NMS1). Des neurones du moteur sont les cibles pathologiques principales, et ce, avec des jonctions neuromusculaires (JNMs), ils jouent, en avance, un rôle significatif dans la pathogénie de AMS. Des études précédentes démontrent qu’une réduction pathologique de niveaux de NMS peut mener aux défauts importants de réorganisation tant dans l’excroissance axonale que dans l’agrégation du récepteur de l’acétylcholine (AChR) sous la terminaison nerveuse dans des modèles de souris. Cependant, si cette reduction pathologique de NMS mène aux caractéristiques infracliniques n’a pas été à l’étude. Ici, nous avons employé le NMS2B/2B et NMS +/- des modèles de souris afin de déterminer si une pathologie semblable à l’AMS est présente infracliniquement, ainsi s’il y a présence de quelconque compensation. Nous montrons une diminution dans le nombre des neurones du moteur dans les modèles de souris, aucun changement de l’épaisseur du myelin et une pathologie modeste de JNM dans les deux modèles de souris. De plus, une compensation par l’expansion de la taille d’unité du moteur est suggérée.

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Antiandrogen Flutamide Protects Male Mice From Androgen-Dependent Toxicity in Three Models of Spinal Bulbar Muscular Atrophy

Endocrinology ◽

10.1210/en.2013-1756 ◽

2014 ◽

Vol 155 (7) ◽

pp. 2624-2634 ◽

Cited By ~ 9

Author(s):

Kayla J. Renier ◽

Sandra M. Troxell-Smith ◽

Jamie A. Johansen ◽

Masahisa Katsuno ◽

Hiroaki Adachi ◽

...

Keyword(s):

Mouse Models ◽

Therapeutic Potential ◽

Late Onset ◽

Muscular Atrophy ◽

Motor Dysfunction ◽

Male Mice ◽

Therapeutic Value ◽

Spinal Bulbar Muscular Atrophy ◽

Proof Of Principle ◽

Polyq Expansion

Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

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Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

Human Molecular Genetics ◽

10.1093/hmg/ddn156 ◽

2008 ◽

Vol 17 (16) ◽

pp. 2552-2569 ◽

Cited By ~ 264

Author(s):

Shingo Kariya ◽

Gyu-Hwan Park ◽

Yuka Maeno-Hikichi ◽

Olga Leykekhman ◽

Cathleen Lutz ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Mouse Models ◽

Neuromuscular Junctions ◽

Muscular Atrophy ◽

Smn Protein

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Spinal Bulbar Muscular Atrophy, Kennedy Disease

Genetic Neuromuscular Disorders ◽

10.1007/978-3-319-56454-8_89 ◽

2017 ◽

pp. 353-356

Author(s):

Corrado Angelini

Keyword(s):

Muscular Atrophy ◽

Spinal Bulbar Muscular Atrophy

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Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2013.07.015 ◽

2014 ◽

Vol 35 (2) ◽

pp. 443.e1-443.e3 ◽

Cited By ~ 8

Author(s):

Pietro Fratta ◽

Toby Collins ◽

Sally Pemble ◽

Suran Nethisinghe ◽

Anny Devoy ◽

...

Keyword(s):

Muscular Atrophy ◽

Sequencing Analysis ◽

Cag Expansion ◽

Spinal Bulbar Muscular Atrophy

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Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy

Asian Journal of Andrology ◽

10.4103/aja.aja_37_21 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0

Author(s):

Takeo Kosaka ◽

Hiroshi Hongo ◽

Hideyuki Hayashi ◽

Kohei Nakamura ◽

Hiroshi Nishihara ◽

...

Keyword(s):

Prostate Cancer ◽

Muscular Atrophy ◽

Brca2 Mutation ◽

Aggressive Prostate Cancer ◽

Spinal Bulbar Muscular Atrophy

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Juvenile Huntington’s Disease and Other PolyQ Diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic and Proteomic Data

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.642773 ◽

2021 ◽

Vol 9 ◽

Author(s):

Karolina Świtońska-Kurkowska ◽

Bart Krist ◽

Joanna Delimata ◽

Maciej Figiel

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Muscular Atrophy ◽

Expression Patterns ◽

Cag Repeat ◽

Human Cognition ◽

Expression Data ◽

Neuronal Stem Cell ◽

Polyq Diseases

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. In addition, we extended our bioinformatic transcriptomic analysis by proteomics data. We identified a group of 13 commonly downregulated genes and proteins in HD mouse models. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.

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