Biology subjects

Vrailas-Mortimer, A.

Publications and source records attributed to Vrailas-Mortimer, A..

4 recordsLinked to original sources

bioRxiv2026

Context-dependent ATP7 Interactions with Parkinson's Disease-associated Genes Modulate Copper Homeostasis Phenotypes

Copper is an essential micronutrient required by enzymes that catalyze oxygen-dependent reactions, but toxic in excess. Mutations in the ATP7A and ATP7B copper transporters cause neuropsychiatric symptoms and neurodegeneration by mechanisms that remain to be elucidated. We previously reported that the ATP7A biochemical interactome is enriched in Parkinsons disease (PD) and neurodegeneration associated proteins, yet the functional outcomes of these interactions are unknown. Using Drosophila, we tested genetic interactions between ATP7 mutants that alter copper levels and a subset of these PD and neurodegeneration causative genes and found sex differences with some candidate genes enhancing ATP7 deleterious phenotypes in both sexes, while others were sex specific. Most notably, we found that Lrrk2 (Lrrk), the most commonly mutated gene in familial forms of PD, protects against ATP7 dysfunction in epidermal epithelial cells with a stronger effect in males than females. However, in dopaminergic neurons Lrrk plays a role in intracellular copper induced toxicity in females but not males, supporting context dependent interactions between ATP7A and PD-associated genes to protect against disruptions in copper homeostasis. Summary StatementWe performed a genetic interaction screen to explore the relationship between copper homeostasis and Parkinsons disease and other neurodegeneration associated genes.

genetics↗

bioRxiv2020

Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content

Rare genetic diseases preponderantly affect the nervous system with phenotypes spanning from neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate conserved interactions between ATP7 paralogs with the COG complex, a Golgi complex tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, catecholaminergic, sensory, and motor neurons. Prominent among neuronal phenotypes was a decreased mitochondrial content at synapses, a phenotype that paralleled with alterations of synaptic morphology, transmission, and plasticity. These neuronal and synaptic phenotypes caused by transgenic expression of ATP7 were rescued by downregulation or haploinsufficiency of COG complex subunits. We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses. Significance StatementMenkes and Wilson disease affect copper homeostasis and characteristically afflict the nervous system. However, their molecular neuropathology mechanisms remain mostly unexplored. We demonstrate that copper homeostasis in neurons is maintained by two factors that localize to the Golgi apparatus, ATP7 and the COG complex. Disruption of these mechanisms affect mitochondrial function and localization to synapses as well as neurotransmission and synaptic plasticity. These findings suggest a new principle of interorganelle communication whereby the Golgi apparatus and mitochondria are functionally coupled through homeostatically controlled cellular copper levels.

neuroscience↗

bioRxiv2019

Evolution of p38 MAP Kinases in Drosophila

As organisms are constantly exposed to the damaging effects of oxidative stress through both environmental exposure as well as internal metabolic processes, they have evolved a variety of mechanisms to cope with this stress. One such mechanism is the highly conserved p38 MAPK (p38K) pathway, which is known to be to post-translationally activated in response to oxidative stress resulting in the activation of downstream antioxidant targets. However, little is known about the role of p38K transcriptional regulation in response to oxidative stress. Therefore, we analyzed the p38K gene family across the genus Drosophila to identify conserved regulatory elements. We find that oxidative stress exposure results in increased p38K protein levels in multiple Drosophila species and is associated with increased oxidative stress resistance. We also find that the p38Kb genomic locus includes conserved binding sites for the AP-1 and lola-PT transcription factors. Accordingly, over-expression of these transcription factors in D. melanogaster is sufficient to induce transcription of p38Kb and enhances resistance to oxidative stress. We further find that the presence of a lola-PT binding site in the p38Kb locus of a given species is predictive of the species survival in response to oxidative stress. Through our comparative genomics approach, we have identified biologically relevant transcription factor binding sites that regulate the expression of p38Kb and are associated with resistance to oxidative stress. These findings reveal a novel mode of regulation for p38K genes and suggests that transcription may play as important a role in p38K mediated stress responses as post-translational modifications. Significance StatementOrganisms encounter a variety of environmental stresses such as oxidative stress throughout their lifetime. Therefore, organisms have evolved a number of mechanisms to combat these stresses. In order to understand how these mechanisms evolved, we have compared the genomes of a diverse set of species across the genus Drosophila to examine the p38 MAPK stress response gene family. Our analysis was able to successfully predict transcription factors that not only regulate our target gene, p38Kb, but do so under different conditions to ensure an appropriate stress response. Therefore, we find that in addition to post-translational regulation, transcriptional regulation of signaling pathways may also play an important role in how organisms are able to adapt to stressful environments or respond to stress conditions as they arise. Furthermore, our comparative genomics approach may be utilized to identify transcriptional regulators of other highly conserved signaling pathways.

evolutionary biology↗

bioRxiv2019

Drosophila p38 MAPK Interacts with BAG-3/starvin to Regulate Age-dependent Protein Homeostasis

As organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with the Chaperone-Assisted Selective Autophagy complex. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex.

genetics↗