Biology subjects

Lima, R. R.

Publications and source records attributed to Lima, R. R..

2 recordsLinked to original sources

bioRxiv2026

Motor sequence analysis as a sensitive biomarker of dopaminergic degeneration in a non-human primate model of parkinsonism

Parkinsons disease is characterized by progressive dopaminergic degeneration, yet motor symptoms emerge only after substantial neuronal loss - a dissociation that challenges the sensitivity of conventional behavioral endpoints in preclinical models. Here, we present a proof-of-principle study establishing a graded hemiparkinsonism model in adult male capuchin monkeys (Sapajus apella) through unilateral, MRI-guided stereotaxic injection of 6-hydroxydopamine into the substantia nigra pars compacta. Three toxin concentrations (4, 10, and 40 mg/mL; n = 3) were tested alongside a vehicle-injected sham control (n = 1). Motor function was assessed longitudinally before and after surgery using a three-task battery comprising the Staircase test, Tube test, and Brinkman board, capturing complementary dimensions of motor functions, including gross lateralization, forelimb use asymmetry, and fine digit coordination. Critically, we introduce a novel sequence-deviation metric applied to Brinkman board performance data to quantify disruption in the spatial organization of pellet retrieval independently of task success. Post-surgical tyrosine hydroxylase immunohistochemistry combined with optical fractionator stereology revealed ipsilateral dopaminergic cell losses of 47%, 59%, and 44% relative to the contralateral hemisphere across the three treated animals, with the sham showing no meaningful hemispheric difference. Behavioral impairments were heterogeneous and strategy-dependent: task completion rates were largely preserved, whereas fine motor strategy analysis revealed post-lesion increases in retrieval sequence disorganization in two of three animals. Exploratory regression analyses suggested that strategy-level metrics were more sensitive to nigrostriatal degeneration than global performance measures. These findings demonstrate that capuchin monkeys subjected to unilateral 6-hydroxydopamine lesions reproduce clinically relevant features of hemiparkinsonism and that motor sequence analysis constitutes a sensitive readout of subclinical dopaminergic dysfunction, and can outperform conventional performance-based metrics detecting early motor alterations, therefore a potential biomarker of subclinical dopaminergic dysfunction, with implications for early detection paradigms in Parkinsons disease research.

neuroscience↗

bioRxiv2026

Src-dependent tyrosine-phosphorylation of NM2A has a protective role against bacterial pore-forming toxins

Pore-forming toxins (PFTs) are key bacterial virulence factors that disrupt host plasma membrane (PM) integrity, triggering cellular stress and initiating repair mechanisms. The cytolysin Listeriolysin O (LLO), secreted by Listeria monocytogenes, has well established roles in infection, yet the host signaling responses to LLO-induced damage remain poorly understood. Here, we identify a previously unrecognized protective pathway in which LLO triggers rapid activation of the tyrosine kinase Src, leading to phosphorylation of the non-muscle myosin II heavy chain NMHC2A at tyrosine 158. While Src activation and NMHC2A tyrosine phosphorylation have been observed during Listeria infection, we demonstrate here that both responses are directly driven by LLO. This phosphorylation event does not alter NMHC2A motor activity in vitro but is required for cytoskeletal reorganization and efficient responses to PM damage. Using Caenorhabditis elegans, we further show that phosphorylation of the NMHC2A homolog NMY-2 at the conserved tyrosine 163 is required for survival under PFT-induced stress and heat shock, revealing an evolutionarily conserved defense mechanism. Together, our findings establish Src-mediated NMHC2A phosphorylation as a critical link between PFT-induced PM damage sensing and actomyosin remodeling, advancing our understanding of host defense against bacterial toxins. Author SummaryPathogenic bacteria often produce toxins that create pores in the membranes of host cells, compromising cell survival and helping the infection spread. To counter this, host cells must quickly detect and repair the damage. We studied how cells respond to Listeriolysin O (LLO), produced by the human pathogenic bacterium Listeria monocytogenes. We found that LLO activates the host Src kinase, which in turn modifies a key structural protein, non-muscle myosin II (NMII). Although this modification does not affect NMIIs normal motor function, it is crucial for organizing the cellular skeleton and protecting the cells membrane after toxin damage. Importantly, we found that this protective mechanism is conserved in the worm Caenorhabditis elegans, where it also defends against a similar bacterial toxin and even heat stress. Our findings reveal a new way that cells use existing structural proteins to rapidly respond to external threats, providing insight into how organisms protect themselves from harmful microbes and environmental stress.

microbiology↗