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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-34360794

RESUMEN

Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.


Asunto(s)
Neuronas Motoras/enzimología , Atrofia Muscular Espinal/enzimología , Unión Neuromuscular/enzimología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Modelos Animales de Enfermedad , Activación Enzimática , Ratones , Ratones Transgénicos , Neuronas Motoras/patología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Unión Neuromuscular/genética , Unión Neuromuscular/patología , Proteínas Tirosina Quinasas Receptoras/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo
2.
RMD Open ; 6(3)2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33115768

RESUMEN

INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal disorder that manifests as peripheral arthritis, dactylitis, enthesitis and spondylitis. PsA results in significant burden that impacts quality of life of patients. We examined the signs, symptoms and impacts reported by patients with PsA, to characterise the patient experience of PsA and develop a conceptual model representing this patient experience. METHODS: Semi-structured interviews were conducted with patients with PsA recruited through the FORWARD databank. Spontaneous and probed signs, symptoms and impacts of PsA were assessed. Patients rated the disturbance of these concepts on their lives using a scale from 0 ('does not disturb') to 10 ('greatly disturbs'). Signs, symptoms and impacts reported by >80% of patients with a disturbance rating of ≥5 were defined as salient concepts. Recruitment continued until concept saturation was achieved. RESULTS: 19 patients with PsA were interviewed. The interviews elicited 42 symptoms of which 8 had not been identified in a previous literature review encompassing 15 relevant articles. The most salient signs and symptoms elicited in the interviews were joint pain, skin symptoms, stiffness, swollen/inflamed joints and fatigue all with moderate to high disturbance ratings (range: 5.5-7.8). The most salient impacts were sleep disturbance, physical disability, effects on daily activities and feelings of frustration with also moderate to high disturbance ratings (range: 6.1-7.4). CONCLUSIONS: The interviews highlighted the adverse impact PsA has on the patient's life and may inform on outcome variables or areas suitable to be assessed in PsA studies.


Asunto(s)
Artritis Psoriásica , Artritis Psoriásica/diagnóstico , Enfermedad Crónica , Humanos , Modelos Teóricos , Calidad de Vida
3.
Elife ; 72018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29460776

RESUMEN

In amyotrophic lateral sclerosis (ALS) and animal models of ALS, including SOD1-G93A mice, disassembly of the neuromuscular synapse precedes motor neuron loss and is sufficient to cause a decline in motor function that culminates in lethal respiratory paralysis. We treated SOD1-G93A mice with an agonist antibody to MuSK, a receptor tyrosine kinase essential for maintaining neuromuscular synapses, to determine whether increasing muscle retrograde signaling would slow nerve terminal detachment from muscle. The agonist antibody, delivered after disease onset, slowed muscle denervation, promoting motor neuron survival, improving motor system output, and extending the lifespan of SOD1-G93A mice. These findings suggest a novel therapeutic strategy for ALS, using an antibody format with clinical precedence, which targets a pathway essential for maintaining attachment of nerve terminals to muscle.


Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Anticuerpos/administración & dosificación , Factores Inmunológicos/administración & dosificación , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/fisiología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Resultado del Tratamiento
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