Cellular and Molecular Neuroscience, Multidisciplinary, Developmental Neuroscience
30
Scopus Publications
1484
Scholar Citations
19
Scholar h-index
22
Scholar i10-index
Scopus Publications
Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons Jose Norberto S. Vargas, Anna-Leigh Brown, Kai Sun, Cathleen Hagemann, Bethany Geary, David Villarroel-Campos, Sam Bryce-Smith, Matteo Zanovello, Madeline Lombardo, Stan Majewski, Andrew Tosolini, Maria Secrier, Matthew J. Keuss, Andrea Serio, James N. Sleigh, Pietro Fratta, Giampietro Schiavo Science Signaling, 2026 The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i 3 LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i 3 LMNs revealed that BDNF temporally regulated the expression and RNA stability of functionally distinct transcriptional programs that included regeneration-associated gene sets, further enhancing their expression. BDNF also regulated the phosphorylation of multiple proteins involved in cytoskeletal dynamics. In compartmentalized cultures of neurons, in which microfluidic chambers isolate somata from their axons, BDNF-induced regeneration depended on axon-specific activation of the ERK-RSK-S6K kinase pathway. The findings show that extrinsic BDNF signaling coordinates intrinsic axon-regeneration programs and highlight the role of spatially regulated kinase activation in this process.
ALS: a field in motion Ruben J. Cauchi, Andrew P. Tosolini Scientific Reports, 2025 Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder driven by complex interactions among genetic, environmental, developmental, and resilience-related factors. The studies in this Scientific Reports’ Collection highlight major advances across diverse domains that collectively broaden our understanding of ALS pathogenesis. Genetic insights emphasise the need for functional validation, as shown by the non-pathogenic behaviour of the KIF5A P986L variant in Drosophila. Neuroimaging findings reveal hypothalamic atrophy in primary lateral sclerosis, underscoring widespread extra-motor involvement. Epidemiological analyses propose that early-life exposures may form the initial steps in a multistage pathway to ALS, while geographic correlations between ALS and multiple sclerosis suggest shared environmental determinants. Experimental model innovations demonstrate selective muscle preservation in SOD1-G93A mice and introduce electrical impedance myography as a sensitive detection method in zebrafish. Mechanistic work shows that stress influences ALS through PI3K/Akt and focal adhesion pathways, linking environment to cellular vulnerability. Finally, cognitive and brain reserve emerge as important modifiers of disease expression and progression. Together, these studies illustrate ALS as a multisystem, lifespan-spanning disorder shaped by both vulnerability and resilience. Their integration offers a forward-looking framework for advancing biomarker discovery, mechanistic research, and therapeutic development in ALS.
Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in mice with advanced age David Villarroel-Campos, Elena R. Rhymes, Andrew P. Tosolini, Bilal Malik, Alessio Vagnoni, Giampietro Schiavo, James N. Sleigh Neurobiology of Aging, 2025 A healthy nervous system is reliant upon an efficient transport network to deliver essential cargoes throughout the extensive and polarised architecture of neurons. The trafficking of cargoes, such as organelles and proteins, is particularly challenging within the long projections of neurons, which, in the case of axons, can be more than four orders of magnitude longer than cell bodies. It is therefore unsurprising that disruptions in axonal transport have been reported across neurological diseases. A decline in this essential process has also been identified in many aging models, perhaps compounding age-related neurodegeneration. Via intravital imaging, we recently determined that, despite a reduction in overall motility, the run speed and displacement of anterograde mitochondrial transport were unexpectedly enhanced in 19-22 month-old mouse peripheral nerves. Here, to determine how aging impacts a different axonal cargo, we evaluated in vivo trafficking of signalling endosomes in motor axons of mouse sciatic nerves from 3 to 22 months. Contrasting with mitochondria, we did not detect alterations in signalling endosome speed, but found a consistent rise in pausing that manifested after 18 months. We then treated muscles with brain-derived neurotrophic factor (BDNF), which regulates axonal transport of signalling endosomes in motor neurons; however, we observed no change in the processivity defect at 22 months, consistent with downregulation of the BDNF receptor TrkB at the neuromuscular junction. Together, these findings indicate that aging negatively impacts signalling endosome trafficking in motor axons, likely through dampened BDNF signalling at the motor neuron-muscle interface.
The node of Ranvier influences the in vivo axonal transport of mitochondria and signaling endosomes Andrew P. Tosolini, Federico Abatecola, Samuele Negro, James N. Sleigh, Giampietro Schiavo Iscience, 2024 Efficient long-range axonal transport is essential for maintaining neuronal function, and perturbations in this process underlie severe neurological diseases. Nodes of Ranvier (NoR) are short, specialized unmyelinated axonal domains with a unique molecular and structural composition. Currently, it remains unresolved how the distinct molecular structures of the NoR impact axonal transport dynamics. Using intravital time-lapse microscopy of sciatic nerves in live, anesthetized mice, we reveal (1) similar morphologies of the NoR in fast and slow motor axons, (2) signaling endosomes and mitochondria accumulate specifically at the distal node, and (3) unique axonal transport profiles of signaling endosomes and mitochondria transiting through the NoR. Collectively, these findings provide important insights into the fundamental physiology of peripheral nerve axons, motor neuron subtypes, and diverse organelle dynamics at the NoR. Furthermore, this work has relevance for several pathologies affecting peripheral nerves and the NoR.
Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice James N. Sleigh, David Villarroel-Campos, Sunaina Surana, Tahmina Wickenden, Yao Tong, Rebecca L. Simkin, Jose Norberto S. Vargas, Elena R. Rhymes, Andrew P. Tosolini, Steven J. West, Qian Zhang, Xiang-Lei Yang, Giampietro Schiavo Jci Insight, 2023 Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.
BDNF-dependent modulation of axonal transport is selectively impaired in ALS Andrew P. Tosolini, James N. Sleigh, Sunaina Surana, Elena R. Rhymes, Stephen D. Cahalan, Giampietro Schiavo Acta Neuropathologica Communications, 2022 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.
Hydrogen peroxide induced by nerve injury promotes axon regeneration via connective tissue growth factor Samuele Negro, Fabio Lauria, Marco Stazi, Toma Tebaldi, Giorgia D’Este, Marco Pirazzini, Aram Megighian, Francesca Lessi, Chiara M. Mazzanti, Gabriele Sales, Chiara Romualdi, Silvia Fillo, Florigio Lista, James N. Sleigh, Andrew P. Tosolini, Giampietro Schiavo, Gabriella Viero, Michela Rigoni Acta Neuropathologica Communications, 2022 Regeneration of the neuromuscular junction (NMJ) leverages on extensive exchange of factors released from motor axon terminals (MATs), muscle fibers and perisynaptic Schwann cells (PSCs), among which hydrogen peroxide (H2O2) is a major pro-regenerative signal. To identify critical determinants of NMJ remodeling in response to injury, we performed temporal transcriptional profiling of NMJs from 2 month-old mice during MAT degeneration/regeneration, and cross-referenced the differentially expressed genes with those elicited by H2O2 in SCs. We identified an enrichment in extracellular matrix (ECM) transcripts, including Connective Tissue Growth Factor (Ctgf), which is usually expressed during development. We discovered that Ctgf levels are increased in a Yes-associated protein (YAP)-dependent fashion in response to rapid, local H2O2 signaling generated by stressed mitochondria in the injured sciatic nerve, a finding highlighting the importance of signals triggered by mechanical force to motor nerve repair. Through sequestration of Ctgf or inactivation of H2O2, we delayed the recovery of neuromuscular function by impairing SC migration and, in turn, axon-oriented re-growth. These data indicate that H2O2 and its downstream effector Ctgf are pro-regenerative factors that enable axonal growth, and reveal a striking ECM remodeling process during nerve regeneration upon local H2O2 signaling. Our study identifies key transcriptomic changes at the regenerating NMJ, providing a rich source of pro-regenerative factors with potential for alleviating the consequences of peripheral nerve injuries.
Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons Elena R. Rhymes, Andrew P. Tosolini, Alexander D. Fellows, William Mahy, Neil Q. McDonald, Giampietro Schiavo Cell Death and Disease, 2022 Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1G93A mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1G93A mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1G93A motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1G93A mice, promoting RET as a potential therapeutic target in the treatment of ALS.
Editorial: Dysfunction and Repair of Neural Circuits for Motor Control Andrew Paul Tosolini, George Z. Mentis, John H. Martin Frontiers in Molecular Neuroscience, 2021 EDITORIAL article Front. Mol. Neurosci., 22 March 2021Sec. Brain Disease Mechanisms https://doi.org/10.3389/fnmol.2021.669824
The evolution of the axonal transport toolkit Sunaina Surana, David Villarroel‐Campos, Oscar M. Lazo, Edoardo Moretto, Andrew P. Tosolini, Elena R. Rhymes, Sandy Richter, James N. Sleigh, Giampietro Schiavo Traffic, 2020
Axonal transport and neurological disease James N. Sleigh, Alexander M. Rossor, Alexander D. Fellows, Andrew P. Tosolini, Giampietro Schiavo Nature Reviews Neurology, 2019
Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition Ashley L. Kalinski, Amar N. Kar, John Craver, Andrew P. Tosolini, James N. Sleigh, Seung Joon Lee, Alicia Hawthorne, Paul Brito-Vargas, Sharmina Miller-Randolph, Ryan Passino, Liang Shi, Victor S.C. Wong, Cristina Picci, Deanna S. Smith, Dianna E. Willis, Leif A. Havton, Giampietro Schiavo, Roman J. Giger, Brett Langley, Jeffery L. Twiss Journal of Cell Biology, 2019
Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons JNS Vargas, AL Brown, K Sun, C Hagemann, B Geary, ... Science Signaling 19 (933), eadx6752 , 2026 2026
Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice G Price, G de Azambuja, C Williams, D Thompson, C Tibbit, Z Ali, A Austin, ... 2026
ALS: a field in motion RJ Cauchi, AP Tosolini Scientific Reports 15 (1), 44791 , 2025 2025 Citations: 1
In vivo axonal transport of mitochondria and signalling endosomes is impaired in fast α-mοtοr neurons in MND mice AP Tosolini, ST Ngo, G Schiavo Theme: Towards Precision in ALS/MND Treatments and Care , 2025 2025
Innervation and cargo-specific axonal transport impairments in FUS-ALS mice with gain and loss of function RL Simkin, AP Tosolini, A Mikheenko, AM Ule, W Jin, B Kalmar, M Ahmed, ... bioRxiv, 2025.06. 16.659513 , 2025 2025
Path Towards Scientific Independence AP Tosolini 2025
Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in mice with advanced age D Villarroel-Campos, ER Rhymes, AP Tosolini, B Malik, A Vagnoni, ... Neurobiology of Aging , 2025 2025 Citations: 5
Metabolic alterations in the absence of a detectable neuromuscular phenotype in novel genomically humanised SOD1A4Vmice. D Thompson, C Williams, AP Tosolini, J Gilthorpe, G Schiavo, EMC Fisher, ... bioRxiv , 2025 2025 Citations: 1
CNTF specifically slows down the axonal transport of signalling endosomes ER Rhymes, JN Sleigh, G Schiavo, AP Tosolini bioRxiv, 2025.10. 09.681259 , 2025 2025
Assessing in vivo axonal transport of mitochondria and signalling endosomes in distinct α-motor neuron subtypes in SOD1G93A mice AP Tosolini, ST Ngo, G Schiavo 2024
The node of Ranvier influences the in vivo axonal transport of mitochondria and signaling endosomes AP Tosolini, F Abatecola, S Negro, JN Sleigh, G Schiavo iScience 27 (11), 111158 , 2024 2024 Citations: 8
In vivo axonal transport of mitochondria and signalling endosomes at the node of Ranvier AP Tosolini, F Abatecola, S Negro, JN Sleigh, G Schiavo 2024
BDNF-dependent modulation of axonal transport is selectively impaired in Motor Neuron Disease AP Tosolini, JN Sleigh, S Surana, ER Rhymes, SD Cahalan, G Schiavo 2023
In vivo axonal transport of diverse organelles in ALS AP Tosolini, N Birsa, T Cunningham, E Fisher, P Fratta, G Schiavo 2023
BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration JNS Vargas, AL Brown, K Sun, C Hagemann, B Geary, ... bioRxiv, 2023.11. 06.565775 , 2023 2023 Citations: 5
Gene Therapy for the Central and Peripheral Nervous System: Volume II AP Tosolini, GM Smith Frontiers in Molecular Neuroscience 16, 1258458 , 2023 2023
Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice JN Sleigh, D Villarroel-Campos, S Surana, T Wickenden, Y Tong, ... JCI insight 8 (9), e157191 , 2023 2023 Citations: 26
Brain-derived neurotrophic factor amplifies neuron-intrinsic programs to enhance axonal regeneration in human motor neurons JN Vargas, AL Brown, K Sun, C Hagemann, B Geary, ... 2023 Citations: 1
Axonal transport in MND AP Tosolini 2023
In vivo axonal transport of diverse organelles in MND AP Tosolini, JN Sleigh, S Surana, ER Rhymes, N Birsa, T Cunningham, ... 2023
MOST CITED SCHOLAR PUBLICATIONS
Axonal transport and neurological disease JN Sleigh, AM Rossor, AD Fellows, AP Tosolini, G Schiavo Nature Reviews Neurology 15 (12), 691-703 , 2019 2019 Citations: 376
Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition AL Kalinski, AN Kar, J Craver, AP Tosolini, JN Sleigh, SJ Lee, ... Journal of Cell Biology 218 (6), 1871-1890 , 2019 2019 Citations: 129
Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes JN Sleigh, AP Tosolini, D Gordon, A Devoy, P Fratta, EMC Fisher, ... Cell Reports 30 (11), 3655-3662. e2 , 2020 2020 Citations: 101
Spatial characterization of the motor neuron columns supplying the rat forelimb AP Tosolini, R Morris Neuroscience 200, 19-30 , 2012 2012 Citations: 98
The travel diaries of tetanus and botulinum neurotoxins S Surana, AP Tosolini, IFG Meyer, AD Fellows, SS Novoselov, G Schiavo Toxicon 147, 58-67 , 2018 2018 Citations: 96
Impaired arpeggio movement in skilled reaching by rubrospinal tract lesions in the rat: a behavioral/anatomical fractionation R Morris, AP Tosolini, JD Goldstein, IQ Whishaw Journal of neurotrauma 28 (12), 2439-2451 , 2011 2011 Citations: 69
Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis AP Tosolini, JN Sleigh Frontiers in Molecular Neuroscience 10 , 2017 2017 Citations: 68
BDNF-dependent modulation of axonal transport is selectively impaired in ALS AP Tosolini, JN Sleigh, S Surana, ER Rhymes, SD Cahalan, G Schiavo Acta Neuropathologica Communications 10 (1), 121 , 2022 2022 Citations: 63
Targeting the full length of the motor end plate regions in the mouse forelimb increases the uptake of Fluoro-Gold into corresponding spinal cord motor neurons AP Tosolini, R Mohan, R Morris Frontiers in neurology 4 , 2013 2013 Citations: 58
Targeting the motor end plates in the mouse hindlimb gives access to a greater number of spinal cord motor neurons: an approach to maximize retrograde transport R Mohan, AP Tosolini, R Morris Neuroscience 274, 318-330 , 2014 2014 Citations: 57
Segmental distribution of the motor neuron columns that supply the rat hindlimb: A muscle/motor neuron tract-tracing analysis targeting the motor end plates R Mohan, AP Tosolini, R Morris Neuroscience 307, 98-108 , 2015 2015 Citations: 56
In vivo imaging of anterograde and retrograde axonal transport in rodent peripheral nerves JN Sleigh, AP Tosolini, G Schiavo Axon Degeneration: Methods and Protocols, 271-292 , 2020 2020 Citations: 38
The evolution of the axonal transport toolkit S Surana, D Villarroel‐Campos, OM Lazo, E Moretto, AP Tosolini, ... Traffic 21 (1), 13-33 , 2020 2020 Citations: 33
Intramuscular delivery of gene therapy for targeting the nervous system AP Tosolini, JN Sleigh Frontiers in Molecular Neuroscience 13, 129 , 2020 2020 Citations: 31
Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice JN Sleigh, D Villarroel-Campos, S Surana, T Wickenden, Y Tong, ... JCI insight 8 (9), e157191 , 2023 2023 Citations: 26
Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons Elena R. Rhymes, Andrew P. Tosolini, Alexander D. Fellows, William Mahy ... Cell Death Disease 13 (584) , 2022 2022 Citations: 24
Assessing rat forelimb and hindlimb motor unit connectivity as objective and robust biomarkers of spinal motor neuron function ME Harrigan, AR Filous, AP Tosolini, R Morris, JM Schwab, WD Arnold Scientific Reports 9 (1), 16699 , 2019 2019 Citations: 24
Targeting Motor End Plates for Delivery of Adenoviruses: An Approach to Maximize Uptake and Transduction of Spinal Cord Motor Neurons AP Tosolini, R Morris Scientific Reports 6, 33058 , 2016 2016 Citations: 22
Intramuscular Injections Along the Motor End Plates: A Minimally Invasive Approach to Shuttle Tracers Directly into Motor Neurons R Mohan, A Tosolini, R Morris JOVE , 2015 2015 Citations: 22
Hydrogen peroxide induced by nerve injury promotes axon regeneration via connective tissue growth factor S Negro, F Lauria, M Stazi, T Tebaldi, G D’Este, M Pirazzini, A Megighian, ... Acta Neuropathologica Communications 10 (1), 189 , 2022 2022 Citations: 18
