Biology subjects

Pagiazitis, J. G.

Publications and source records attributed to Pagiazitis, J. G..

2 recordsLinked to original sources

bioRxiv2026

A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases

Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification. HighlightsO_LISpinal cord segment-specific analysis reduces variability and allows accurate MN quantification C_LIO_LIChAT is the most reliable MN marker in murine and human spinal cords C_LIO_LIDeep learning-based segmentation enables unbiased MN quantification in intact spinal cords C_LIO_LIMN degeneration is widespread in ALS but restricted to pools innervating proximal muscles in severe SMA C_LI

neuroscience↗

bioRxiv2024

Synaptic imbalance and increased inhibition impair motor function in SMA

Movement is executed through the balanced action of excitatory and inhibitory neurotransmission in motor circuits of the spinal cord. Short-term perturbations in one of the two types of transmission are counteracted by homeostatic changes of the opposing type. Prolonged failure to balance excitatory and inhibitory drive results in dysfunction at the single neuron, as well as neuronal network levels. However, whether dysfunction in one or both types of neurotransmission leads to pathogenicity in neurodegenerative diseases characterized by select synaptic deficits is not known. Here, we used mouse genetics, functional assays, morphological methods, and viral-mediated approaches to uncover the pathogenic contribution of unbalanced excitation-inhibition neurotransmission in a mouse model of spinal muscular atrophy (SMA). We show that vulnerable motor circuits in the SMA spinal cord fail to respond homeostatically to the reduction of excitatory drive and instead increase inhibition. This imposes an excessive burden on motor neurons and further restricts their recruitment to activate muscle contraction. Importantly, genetic or pharmacological reduction of inhibitory synaptic drive improves neuronal function and provides behavioural benefit in SMA mice. Our findings identify the lack of excitation-inhibition homeostasis as a major maladaptive mechanism in SMA, by which the combined effects of reduced excitation and increased inhibition diminish the capacity of premotor commands to recruit motor neurons and elicit muscle contractions.

neuroscience↗