BDNF-dependent modulation of axonal transport is selectively impaired in ALS

Tosolini, AP; Sleigh, JN; Surana, S; Rhymes, ER; Cahalan, Stephen. D; Schiavo, G

Abstract

Axonal transport ensures long-range delivery of essential cargoes between proximal and distal compartments, and is needed for neuronal development, function, and survival. Deficits in axonal transport have been detected at pre-symptomatic stages in the SOD1(G93A) and TDP-43(M337V) mouse models of amyotrophic lateral sclerosis (ALS), suggesting that impairments in this critical process are fundamental for disease pathogenesis. Strikingly, in ALS, fast motor neurons (FMNs) degenerate first whereas slow motor neurons (SMNs) are more resistant, and this is a currently unexplained phenomenon. The main aim of this investigation was to determine the effects of brain-derived neurotrophic factor (BDNF) on in vivo axonal transport in different alpha-motor neuron (MN) subtypes in wild-type (WT) and SOD1(G93A) mice. We report that despite displaying similar basal transport speeds, stimulation of wild-type MNs with BDNF enhances in vivo trafficking of signalling endosomes specifically in FMNs. This BDNF-mediated enhancement of transport was also observed in primary ventral horn neuronal cultures. However, FMNs display selective impairment of axonal transport in vivo in symptomatic SOD1(G93A) mice, and are refractory to BDNF stimulation, a phenotype that was also observed in primary embryonic SOD1(G93A) neurons. Furthermore, symptomatic SOD1(G93A) mice display upregulation of the classical non-pro-survival truncated TrkB and p75(NTR) receptors in muscles, sciatic nerves, and Schwann cells. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in SOD1(G93A) MNs, thus identifying a new key deficit in ALS.

Citation

Tosolini, A., Sleigh, J., Surana, S., Rhymes, E., Cahalan, S. D., & Schiavo, G. (2022). BDNF-dependent modulation of axonal transport is selectively impaired in ALS. Acta Neuropathologica Communications, 10(1), https://doi.org/10.1186/s40478-022-01418-4

• Journal Article Type: Article
• Acceptance Date: Jun 29, 2022
• Online Publication Date: Aug 22, 2022
• Publication Date: 2022
• Deposit Date: Aug 7, 2023
• Publicly Available Date: Aug 7, 2023
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• DOI: https://doi.org/10.1186/s40478-022-01418-4
• Keywords: Axonal transport; Amyotrophic lateral sclerosis; Motor neuron; BDNF; TrkB; p75(NTR); MOTOR-NEURON DEGENERATION; P75 NEUROTROPHIN RECEPTOR; MOUSE MODEL; LOCAL TRANSLATION; SKELETAL-MUSCLE; MUTANT TDP-43; IN-VIVO; TRKB; RAT; DOMAIN