Biology subjects

Low, P.

Publications and source records attributed to Low, P..

3 recordsLinked to original sources

bioRxiv2025

Ubiquitination of secretory granules promotes crinophagic degradation in Drosophila

Gland cells dynamically regulate their secretory granule content via balancing the rates of synthesis, maturation, secretion, and lysosomal degradation (crinophagy). The signal(s) leading to crinophagic breakdown of secretory granules are unknown. Here we show that dynamic ubiquitination of unreleased or low-grade glue-containing secretory granules marks these vesicles for crinophagy in larval salivary gland cells of Drosophila. We identify the ubiquitin ligase Cnot4 and the deubiquitinating enzyme Usp7 as mediators of glue granule ubiquitination and deubiquitination, respectively. Loss of either Cnot4 or Usp7 impairs glue granule fusion with lysosomes. Overexpression of Cnot4 induces premature crinophagy while Usp7 overexpression prevents developmental crinophagy via modulation of glue granule ubiquitination status. Our work establishes that ubiquitination of secretory granules is a key trigger of crinophagy in Drosophila, paving the way for further analysis of this barely characterized degradation route in Metazoans.

cell biology↗

bioRxiv2020

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in the SOD1G93A mouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specific SOD1G93A locomotor deficits. These distinct SOD1G93A locomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbate SOD1G93A locomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.

neuroscience↗

bioRxiv2019

Nimodipine prevents the development of spasticity after spinal cord injury

Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine -- an FDA-approved L-type calcium channel blocker -- starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of CaV 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal CaV 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

pathology↗