BDNF-dependent modulation of axonal transport is selectively impaired in ALS
BDNF-dependent modulation of axonal transport is selectively impaired in ALS
Abstract Axonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments of neurons, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments are fundamental for disease pathogenesis. However, the precise mechanisms responsible for the transport deficits and whether they preferentially affect α-motor neuron (MN) subtypes remain unresolved. Here, we report that stimulation of wild-type neurons with brain-derived neurotrophic factor (BDNF) enhances trafficking of signalling endosomes specifically in fast MNs (FMNs). In early symptomatic SOD1G93A mice, FMNs display selective impairment of axonal transport and develop an insensitivity to BDNF stimulation, with pathology upregulating classical non-pro-survival receptors in muscles and sciatic nerves. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in vulnerable SOD1G93A MNs, thus identifying a new key deficit in ALS amenable for future therapeutic interventions.
Tosolini Andrew P.、Sleigh James N.、Rhymes Elena R.、Cahalan Stephen D.、Surana Sunaina、Schiavo Giampietro
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London||UCL Queen Square Motor Neuron Disease Centre, University College LondonDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London||UCL Queen Square Motor Neuron Disease Centre, University College London||UK Dementia Research Institute, University College LondonDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London||UCL Queen Square Motor Neuron Disease Centre, University College LondonComparative Neuromuscular Disease Laboratory, Department of Clinical Sciences and Services, Royal Veterinary College, University of LondonDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London||UCL Queen Square Motor Neuron Disease Centre, University College London||UK Dementia Research Institute, University College LondonDepartment of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London||UCL Queen Square Motor Neuron Disease Centre, University College London||UK Dementia Research Institute, University College London
神经病学、精神病学基础医学生理学
axonal transportamyotrophic lateral sclerosismotor neuronsBDNFTrkBp75NTRsignalling endosomes
Tosolini Andrew P.,Sleigh James N.,Rhymes Elena R.,Cahalan Stephen D.,Surana Sunaina,Schiavo Giampietro.BDNF-dependent modulation of axonal transport is selectively impaired in ALS[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.12.06.471484.点此复制
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