Biology subjects

Lowe, S. A.

Publications and source records attributed to Lowe, S. A..

4 recordsLinked to original sources

bioRxiv2025

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

Biallelic AAGGG expansions in Replication Factor Complex Subunit 1 (RFC1) are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and are increasingly recognised as a common cause of adult-onset ataxia and sensory neuropathy. However, the disease-causing mechanisms remain unclear. Here we leveraged in vitro assays, post-mortem brain tissue, patient-derived cell lines and a neuronal Drosophila model to demonstrate that AAGGG expansions are associated with tissue-specific reductions in the expression of RFC1 transcript, along with impaired RFC1 function and increased sensitivity to DNA damage from platinum-based drugs. CRISPR/Cas9 excision of the AAGGG repeat and flanking AluSx3 element normalized RFC1 expression in iPSC-derived neurons and rescued the DNA damage response, providing a framework for future therapeutic strategies. We also show that these biological findings are clinically relevant in heterozygous AAGGG expansion carriers, who display an increased risk and severity of neuropathy with platinum-based chemotherapy.

neuroscience↗

bioRxiv2025

Nighttime sleep modulates mechanosensory habituation in Drosophila

Sleep is a highly conserved behaviour that facilitates episodic, procedural, and/or associative modes of memory across species 1-3, a process hypothesised to involve structural downscaling of synapses potentiated during waking episodes 4-6. Habituation, an ancient form of non-associative memory in which repetition of a stimulus leads to diminishing behavioural responses, is considered a prerequisite for such complex forms of learning 7,8. Yet whether sleep also influences the capacity of organisms to habituate is poorly understood. Here we examine this question using the fruit fly, Drosophila. We describe an automated system that yields long-term analogue measurements of habituation to mechanosensory stimuli in adult flies. Using this platform, we find that Drosophila lacking neuronal calcium sensor Neurocalcin - which exhibit reduced sleep specifically during the night 9 - display impaired mechanosensory habituation during the day. Mimicking a method used to treat insomnia 10, we show that compressing nighttime duration both restores consolidated night sleep and renormalises habituation in Neurocalcin mutants. Conversely, in wild type flies without sleep deficits, decreasing night length reduces total night sleep and disrupts daytime habituation. In wild type flies, exposure to longer nights - which increases overall night sleep - enhances synaptic downscaling in sensory circuits. Strikingly, this effect is abolished in Neurocalcin mutants, which do not exhibit increased sleep under these conditions. Collectively, our findings reveal a role for nighttime sleep in facilitating habituation and suggest that this may occur by promoting synaptic downscaling.

neuroscience↗

bioRxiv2025

Micro-/nano-plastics accentuate Parkinson's Disease-relevant phenotypes in a Drosophila model

Micro- and nano-plastic (MNP) particles are a ubiquitous environmental contaminant that are increasingly bioaccumulating in human tissues, particularly the brain. MNPs induce mitochondrial defects, oxidative stress, inflammatory responses and neurotoxicity in cellular and organismal models. This raises the possibility that MNP exposure could cause or exacerbate neurological conditions associated with these pathological phenomena. Parkinsons Disease (PD), a common movement disorder characterised by degeneration of striatal dopaminergic neurons, and associated with mitochondrial dysfunction, represents such a condition. We therefore hypothesised that MNP exposure might interact with PD risk mutations affecting mitochondrial fidelity. We used a fruit fly model of PRKN-dependent PD associated with defects in mitophagy, a mitochondrial quality control pathway, to test this hypothesis. We found that ingestion of MNPs at concentrations tolerated by wild-type controls selectively enhanced PD-relevant phenotypes - including progressive dopaminergic neurodegeneration, movement defects, and sleep disruption - in this model of PD. Our data suggest that defects in mitochondrial quality control can increase vulnerability to MNP exposure, and more broadly, that MNPs may synergistically interact with existing genetic risk factors to worsen neurological disease.

neuroscience↗

bioRxiv2023

BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window

Gain-of-function mutations in BK potassium channels (BK GOF) cause debilitating involuntary limb movements. BK channels modulate action potential shape and neurotransmission in mature neurons, yet some BK GOF mutations also cause neurodevelopmental morbidities. Thus, whether BK GOF impairs limb control by altering the excitation/inhibition of mature motor circuits, or by disrupting their development, remains unclear. To address this issue, we developed a genetic method enabling spatiotemporal control of BK channel expression in neurons of the fruit fly, Drosophila. In concert with high-resolution measurements of limb kinematics, we demonstrate that GOF BK channels act during a narrow neurodevelopmental period to perturb limb control in adult flies. During this period, BK GOF alters synaptic localisation of the key active zone protein Bruchpilot and suppresses excitatory neurotransmission. In a wild-type background, we find that reducing neural activity during neurodevelopment yields similar motor defects to those observed in BK GOF flies. Conversely, enhancing neural excitability during development rescues alterations in limb kinematics in BK GOF flies. Collectively, our results suggest that BK GOF perturbs limb control largely by disrupting activity-dependent aspects of neuronal development.

neuroscience↗