AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in <i>GarsP278KY/+</i> mice

Özeş, Burçak; Moss, Kyle; Myers, Morgan; Ridgley, Alicia; Chen, Lei; Murrey, Douglas A.; Sahenk, Zarife

doi:10.1093/braincomms/fcab252

Cited by 17 publications

(29 citation statements)

References 69 publications

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“…We also assessed the status of NMJ in response to NT-3 gene therapy in this model as there is evidence that changes in endplate morphology and NMJ remodeling occur with aging and precede loss of fast motor units [ 20 ]. Using immunohistochemistry-based parameters [ 11 ], we analyzed a total of 330 NMJs derived from intrinsic foot muscles of NT-3 treated and untreated aged C57BL/6 mice. This analysis showed that AAV1.NT-3 gene therapy, at 6 months of treatment gave rise to a 29.7% increase of innervated NMJs ( p = 0.0123).…”

Section: Resultsmentioning

confidence: 99%

“…Lumbrical muscles collected from treated and untreated mice ( n = 4 for both cohorts with equal sex distribution) were processed as described previously [ 11 ]. Muscles were fixed and stained with primary antibodies (Acetylcholine receptor (AChR) antibody, α Bungarotoxin, T1175, 1:500; Anti Neurofilament 200 antibody, N4142, 1:500; SV2 antibody, AB_2315387, 1:50) [ 49 , 50 ], followed by incubation with secondary antibodies (Alexa Fluor 488 conjugated anti-rabbit and anti-mouse IgG, 1:500).…”

Section: Methodsmentioning

confidence: 99%

“…Samples were imaged at 60× magnification using a Zeiss LSM 800 confocal microscope. NMJs were considered to be innervated when nerve completely overlapped the AChRs, as partially innervated when some parts of the AChRs were not overlapping with nerve, and as denervated when there was not any nerve co localizing with AChRs [ 11 , 51 ]. An average of 41.3 NMJs per mouse were evaluated from NT-3-treated and UT-mice ( n = 4 mice per group with equal sex distribution).…”

Section: Methodsmentioning

confidence: 99%

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AAV1.NT-3 gene therapy prevents age-related sarcopenia

Özeş¹,

Tong²,

Myers³

et al. 2023

Aging

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Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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AAV1.NT-3 gene therapy prevents age-related sarcopenia

Özeş¹,

Tong²,

Myers³

et al. 2023

Aging

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“…The mature neurotrophins then bind to their corresponding receptors, the Trk family of receptor tyrosine kinases, and regulate neuronal survival and synaptic plasticity [100,101]. Aberrant expressions of NT-3 and NT-4/5 participate in pathophysiological conditions including motor dysfunction, cognitive decline, stroke, and SCZ [102][103][104][105][106][107].…”

Section: Other Neurotrophinsmentioning

confidence: 99%

The emerging role of furin in neurodegenerative and neuropsychiatric diseases

Zhang

Gao

Bai

et al. 2022

Transl Neurodegener

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Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer’s disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases.

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“…It also increased both myelin thickness and muscle fiber size and improved the denervated state of NMJ. On the basis of the multiple effects of this molecule, a potential benefit could be predicted in patients with mutations in GARS1 and other aminoacyl tRNA synthetases [55 ▪▪ ]. Zuko et al found that mutant glycyl-tRNA synthetases cause an impairment in mRNA translation elongation and that transgenic tRNA Gly overexpression rescues protein synthesis and peripheral neuropathy in mice and fly models of GARS1-CMT/CMT2D.…”

Section: Treatmentmentioning

confidence: 99%

Hereditary motor neuropathies

Frasquet

Sevilla

2022

Current Opinion in Neurology

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Purpose of reviewDistal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field. Recent findingsDespite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1. Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways. SummaryDespite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials.

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AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice

Cited by 17 publications

References 69 publications

AAV1.NT-3 gene therapy prevents age-related sarcopenia

AAV1.NT-3 gene therapy prevents age-related sarcopenia

The emerging role of furin in neurodegenerative and neuropsychiatric diseases

Hereditary motor neuropathies

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