Biology subjects

Lavelle, M.

Publications and source records attributed to Lavelle, M..

3 recordsLinked to original sources

bioRxiv2025

USP30 inhibition improves mitochondrial health through both PINK1-dependent and independent mechanisms

Mitochondrial dysfunction is a key feature of many pathologies, including Parkinsons disease. The selective vulnerability of dopaminergic neurons is thought to be influenced by mitochondrial dysfunction and mutations in the mitophagy regulating proteins PINK1 and Parkin that are known to cause early-onset Parkinsonism in an autosomal recessive manner. Augmentation of mitophagy through inhibition of USP30 may be a viable therapeutic strategy for a number of diseases including Parkinsons. USP30 inhibition has been demonstrated to augment PINK1/PRKN mitophagy but also potentiate basal mitophagy to support the removal of dysfunctional mitochondria. Therefore, long-term de-regulation of mitophagy has been proposed to lead to mitochondrial depletion. We have used an integrated approach across cell lines, primary neurons and iPSC-derived dopaminergic neuronal cultures to assess the short and long-term effects of USP30 inhibition on mitochondrial health and neuronal activity. We investigated the dependence of USP30 inhibition phenotypes on the PINK1/Parkin pathway using genetic ablation and in iPSC-derived neurons from Parkinsons patients with PINK1 or PRKN mutations. Loss of USP30 through CRISPR/Cas9-mediated knockout resulted in increased basal and depolarisation-induced mitophagy in SH-SY5Y cells. Loss of USP30 or pharmacological inhibition altered mitochondrial morphology and led to increases in membrane potential and ATP levels with decreased oxygen consumption, suggesting that USP30 loss results in a more efficient mitochondrial network. These changes in morphology were found to be independent of PINK1 or Parkin. Chronic pharmacological inhibition of USP30 or CRISPRi-mediated knockdown of USP30 did not impact dopaminergic neuronal activity, as assessed by electrophysiological profiling, but did potentiate depolarisation-induced mitophagy in primary and iPSC-derived neuronal cultures. We observed minimal changes in mitophagy levels in iPSC-derived dopaminergic neurons from Parkinsons patients with PINK1 or PRKN mutations that were independent of the ability to produce p65Ub. Importantly, within this experimental paradigm, pharmacological USP30 inhibition increased depolarisation-induced mitophagy in both PINK1 and PRKN patients to the same extent as control neurons. These results support a role for USP30 in modulating the trigger threshold for mitophagy and suggest that USP30 inhibitors may be beneficial in patients with impairments in PINK1/Parkin-mediated mitophagy.

neuroscience↗

bioRxiv2024

Comparing efficiencies of population control methods for responding to foreign animal disease threats in wild pigs

Introductions of foreign animal diseases (FADs) into free-ranging wildlife can be difficult to control and devastating for domestic livestock trade. Combating a new FAD introduction in wildlife with an emergency response requires quickly limiting spread of the disease by intensely removing wild animals and recovering their carcasses for proper disposal. In the case of African swine fever virus (ASFv) in wild pigs (Sus scrofa), which has been spreading in many regions of the world, there is little information on the time- and cost-efficiency of methods for intensively and consistently removing wild pigs and recovering carcasses in an emergency response scenario. We compared the efficiencies of aerial operations, trapping, an experimental toxic bait, and ground shooting in northcentral Texas, USA during two months in 2023. Removing and recovering carcasses of wild pigs averaged a rate of 0.15 wild pigs/person hour and cost an average of $233.04/wild pig ($USD 2023) across all four methods. Aerial operations required the greatest initial investment but subsequently was the most time- and cost-efficient, costing an average of $7,266 to incrementally reduce the population by 10% including recovering carcasses. Aerial operations required a ground crew of [~]7 people/helicopter to recover carcasses. Costs for reducing the population of wild pigs using trapping were similar, although took 13.5 times longer to accomplish. A benefit of trapping was carcass recovery was incorporated. Toxic baiting was less efficient because carcass recovery required substantial time, and we removed very few wild pigs with ground shooting in this landscape. We recommend combining aerial and trapping methodologies to remove wild pigs and their carcasses efficiently and effectively during a FAD response. Overall, our findings can inform the preparation of resources, personnel needs, and deployment readiness for FAD responses involving wild pigs.

ecology↗

bioRxiv2024

Electrophysiological correlates of visual memory search

In everyday life, we frequently engage in hybrid search, where we look for multiple items stored in memory (e.g., a mental shopping list) in our visual environment. Across three experiments, we used event-related potentials to better understand the contributions of visual working memory (VWM) and long-term memory (LTM) during the memory search component of hybrid search. Experiments 1 and 2 demonstrated that the FN400 - an index of LTM recognition - and the CDA - an index of VWM - increased with memory set size (target load), suggesting that both VWM and LTM are involved in memory search, even when memory load exceeds capacity limitations of VWM. In Experiment 3, we used these electrophysiological indices to test how categorical similarity of targets and distractors affects memory search. The CDA and FN400 were modulated by memory set size only if items resembled targets. This suggests that dissimilar distractor items can be rejected before eliciting a memory search. Together, our findings demonstrate the interplay of VWM and LTM processes during memory search for multiple targets.

neuroscience↗