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AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice

Authors :
Hsin-Hsiung Chen
Hsin-Tung Yeo
Yun-Hsin Huang
Li-Kai Tsai
Hsing-Jung Lai
Yeou-Ping Tsao
Show-Li Chen
Source :
Skeletal Muscle, Vol 14, Iss 1, Pp 1-18 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

Abstract Background Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS. Methods We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice. Results SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice. Conclusions AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

Details

Language :
English
ISSN :
20445040
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Skeletal Muscle
Publication Type :
Academic Journal
Accession number :
edsdoj.80c578ac91c4c2aa3db510bbe57fac1
Document Type :
article
Full Text :
https://doi.org/10.1186/s13395-024-00349-z