Biology subjects

Pirazzini, M.

Publications and source records attributed to Pirazzini, M..

3 recordsLinked to original sources

bioRxiv2025

Spatiotemporal multi-omics atlas of the aging neuromuscular junction

The demographic shift toward a global aging population, coupled with rising prevalence of neurodegenerative diseases, poses major public health challenges. Aging is the primary risk factor for most neurodegenerative conditions, making the elucidation of its molecular mechanisms critical for developing effective interventions. Dysfunction of the neuromuscular junction (NMJ), the specialized synapse essential for motor function, is an early hallmark of aging and several neurodegenerative disorders, yet its molecular determinants remain incompletely understood. To shed light on potential common underlying mechanisms, we performed a spatiotemporal multi-omics analysis of the murine NMJ during aging, uncovering several genes showing decoupling between transcript and protein trajectories that may drive the related progressive motor decline. NMJs of soleus (SOL) and extensor digitorum longus (EDL) muscles, differing in fiber composition and vulnerability to aging and disease, displayed distinct spatiotemporal dynamics: fast-twitch EDL, more susceptible to degeneration, exhibited stronger mRNA-protein decoupling than aged slow-twitch SOL or younger SOL and EDL muscles. Elevated expression of miRNAs and RNA-binding proteins in aged EDL highlights the key role of post-transcriptional regulation in NMJ aging. This study provides new insights into the physiopathology of neuromuscular aging and offers a resource for investigating mechanisms shared between aging and neurodegenerative diseases. Additionally, it opens avenues for AI-driven discovery of drug targets and early biomarkers, potentially accelerating the development of therapeutic strategies.

neuroscience↗

bioRxiv2025

Targeting Neuromuscular Junction Regeneration is a Therapeutic Strategy in ALS

Instability and denervation of the neuromuscular junction (NMJ) are early events in Amyotrophic Lateral Sclerosis (ALS), likely reflecting a progressive decline in the regenerative capacity of motor neurons (MNs) and their environment. To investigate this, we evaluated NMJ regeneration throughout disease progression in SOD1G93A mice following reversible axon terminal degeneration induced by -Latrotoxin. In parallel, we monitored the expression of CXCR4, a GPCR upregulated during axonal regeneration, and tested whether its pharmacological activation could mitigate ALS- related functional decline. We found that NMJ regenerative capacity is largely preserved during pre- and early symptomatic stages, and remains active in subsets of NMJs even at later stages. CXCR4 is expressed at axon terminals from early disease stages, declining only at end stage. Its expression is conserved across ALS models, including SOD1G93A pigs, hiPSC-derived MN with ALS mutations, and biopsies from sporadic ALS patients. CXCR4 stimulation improved motor function, NMJ innervation, MN survival, and respiratory performance in ALS mice, and axon outgrowth in iPSC-derived MN. These findings identify the NMJ and CXCR4 as viable therapeutic targets in ALS.

neuroscience↗

bioRxiv2021

Extremely potent human monoclonal antibodies for the prophylaxis and therapy of Tetanus

Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin protein toxins and as a safe preventive and therapeutic substitute of hyperimmune sera. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which have been extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. Some mechanistic aspects of tetanus neurotoxin intoxication were revealed, explaining at the same time, the unprecedented neutralization ability of these antibodies. Importantly, these antibodies are exceptionally efficient in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralize tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use upon intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.

pathology↗