Coupling axonal mRNA transport and local translation to organelle maintenance and function

Vargas, Jose Norberto S.; Sleigh, James N.; Schiavo, Giampietro

doi:10.1016/j.ceb.2022.01.008

Cited by 20 publications

(22 citation statements)

References 63 publications

(109 reference statements)

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“…However, an important caveat of these analyses is that these mixed cultures contain several neuronal (e.g., α- and γ-MN, as well as cholinergic glutamatergic, glycinergic and GABA-ergic interneurons) and non-neuronal (e.g., different glia and fibroblasts) subtypes. Furthermore, the inability of SOD1 G93A motor neurons to respond to BDNF may be due to multiple mechanisms, including differential recruitment of dynein adapters (e.g., snapin [ 65 ]), as well as their altered local translation [ 3 , 42 , 66 ]. In this regard, we have previously reported that pharmacological inhibition of IGF1R specifically increases the levels of the dynein adaptor BICD1 by promoting its axonal translation [ 7 ], thus restoring physiological transport in SOD1 G93A MNs in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Mutant, but not WT, SOD1 (i.e., SOD1 G93A and SOD1 G85R ) interacts with the dynein motor complex [ 68 ], suggesting that vulnerable FMNs may accumulate more of this pathological protein, thus impinging upon retrograde transport regulation. Mutant SOD1 also aberrantly interacts with the stress granule protein G3BP1 [ 69 ], thus potentially disturbing processes involved in axonal maintenance (e.g., stress granule dynamics, RNA localisation) [ 3 ]. Axonal transport deficits also impact local translation, as Rab7-containing organelles, which include signalling endosomes, are sites for mitochondrial-associated local mRNA translation [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we report that BDNF signalling in SOD1 G93A mice is dysregulated in embryonic ventral horn neurons and that adult MNs are refractory to BDNF stimulation, with TA axons displaying ~ 38% reduction in transport speeds in early symptomatic SOD1 G93A mice (P73). As physiological BDNF and TrkB levels fluctuate (e.g., upon exercise [ 38 ]), persistent BDNF insensitivity can have severe consequences for MN homeostasis, impacting translation and signalling events in axon terminals, along the axon and within MN soma [ 3 , 22 , 38 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although only a small proportion of ALS-causing mutations are found in genes encoding components of the axonal transport machinery (e.g., KIF5A, DCTN1, ANXA11 ), altered axonal transport is a common pathological feature downstream of many ALS-causing mutations [ 1 , 2 ]. Axonal transport maintains neuronal homeostasis by ensuring the long-range delivery of several cargoes, including cytoskeletal components, organelles, signalling molecules and RNA between proximal and distal neuronal compartments [ 3 ]. As a result, perturbations in axonal transport have severe consequences for neuronal homeostasis and function [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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

Tosolini

Sleigh

Surana

et al. 2022

acta neuropathol commun

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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 SOD1G93A and TDP-43M337V 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 α-motor neuron (MN) subtypes in wild-type (WT) and SOD1G93A 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 SOD1G93A mice, and are refractory to BDNF stimulation, a phenotype that was also observed in primary embryonic SOD1G93A neurons. Furthermore, symptomatic SOD1G93A mice display upregulation of the classical non-pro-survival truncated TrkB and p75NTR receptors in muscles, sciatic nerves, and Schwann cells. Altogether, these data indicate that cell- and non-cell autonomous BDNF signalling is impaired in SOD1G93A MNs, thus identifying a new key deficit in ALS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Tosolini

Sleigh

Surana

et al. 2022

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nevertheless, these vital processes are not independent since mRNA must travel from the nucleus to translation sites. In fact, transport and translation are intricately linked through a process called “hitchhiking,” whereby mRNAs are co-transported with organelles through tethering of RNA-binding proteins (RBPs) for on-demand axonal translation (Vargas et al, 2022 ). Accordingly, disruption of transport or translation in axons can impair neurodevelopment and drive neurodegeneration (Costa and Willis, 2018 ; Sleigh et al, 2019 ).…”

mentioning

confidence: 99%