Biology subjects

Allison, K.

Publications and source records attributed to Allison, K..

4 recordsLinked to original sources

bioRxiv2025

AMPK Repositions Early Endosomes via Gapex-5 to Promote Delivery of Iron to Mitochondria

The regulation of the spatial organization of organelles within cells is critical for coordinating signaling, membrane traffic, and metabolite exchange. Metabolic cues regulate the position and function of lysosomes, yet whether and how metabolic signals may similarly regulate other organelles such as early endosomes (EEs) remains unclear. We find that AMP-activated protein kinase (AMPK), a key regulator of metabolic homeostasis activated in response to nutrient scarcity, triggers movement of EEs to the perinuclear region of cells, leading to enhanced proximity of endosomes to mitochondria and increased delivery of iron to mitochondria. The movement of EEs and increased mitochondrial iron content elicited by AMPK activation requires Gapex-5, a GEF for the early endosome Rab5 previously shown to be an AMPK substrate. These findings reveal a mechanism by which AMPK reprograms endosome positioning to facilitate inter-organelle communication and iron delivery to mitochondria to support metabolic adaptation under conditions of nutrient scarcity.

cell biology↗

bioRxiv2025

Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation

Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243A>G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for [~]80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generated a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncovered heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy showed a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.

neuroscience↗

bioRxiv2024

DACIT: Device for Axon - Cancer cell Interaction Testing in 2D and 3D

There is increasing interest in studying the role of peripheral innervation in tumor growth and metastasis. However, in vitro studies of interactions between cancer cells and axonal projections are technically challenging. To address this, we have developed a microfluidic Device for Axon-Cancer cell Interaction Testing in 2D and 3D (DACIT). We show that DACIT successfully separates neuronal soma from the axons and cancer cells into two compartments, which can be exposed to similar, or different growth conditions, depending on the experimental needs. We compare neoaxonogenesis using either the PC-12 cell line or primary embryonic or adult sensory neurons, demonstrating superior neurite growth in primary cells. Additionally, we show that DACIT can accommodate assessing growth and 3D invasion of tumor spheroids, due to its unique height profile. Hence, DACIT can be used to analyze cancer cell interactions with axons in most typical cell biology assays such as proliferation, invasion, and calcium activity which we demonstrate on examples of imaging transients in GCaMP6-labeled neurons, invadopodia assay, and 3D cancer spheroid invasion.

cancer biology↗

bioRxiv2019

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Human brain transcriptomes can highlight biological pathways associated with Alzheimers disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 AD-associated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age- and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntingtons disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

systems biology↗