Biology subjects

Hannan, S. B.

Publications and source records attributed to Hannan, S. B..

5 recordsLinked to original sources

bioRxiv2025

Revealing the nervous system requirements of Alzheimer disease risk genes in Drosophila

Most Alzheimers disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom, loss-of-function alleles for each of the conserved fly orthologs. Most of the genes (80%) are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of function causes neurodegeneration (e.g., Snx6/SNX32 and ClC-a/CLCN1), 35 required for neurophysiology (e.g., Arr1/ARRB2, stai/STMN4), and 8 with diminished CNS resilience following a thermal or mechanical stress (e.g., cindr/CD2AP, Amph/BIN1). In a parallel screen, we found 28 AD risk gene homologs (e.g, Ets98B/SPI1, Yod1/YOD1) that modify the neurotoxicity of either amyloid-{beta} peptide or tau protein, which aggregate to form AD pathology. To translate our findings back to human AD, we developed and deployed oligogenic risk scores based on gene clusters with shared nervous system phenotypes in flies, pinpointing functional pathways that differentially drive AD risk. Our results--available online via the Alzheimers Locus Integrative Cross-species Explorer (alice.nrihub.org)--reveal novel nervous system requirements for dozens of AD risk genes and may enable dissection of causal heterogeneity in AD.

genetics↗

bioRxiv2025

Hippocampal circuit-specific enhancement of GABA-inhibition caused by discrete gene regions in a Down syndrome model

Although Down syndrome (DS), trisomy 21, affects [~]6 million people worldwide, the neural circuit mechanisms underlying the neurophenotypes of impaired learning, memory and language are unknown. A prominent candidate mechanism involves dysfunctional GABA-signalling and GABAA receptor ligands have been proposed as therapeutics to reverse the neurophenotypic effects of DS. By investigating GABA neurotransmission in brain regions important for cognition in mouse DS models, we reveal that excessive inhibition is not a ubiquitous feature of DS but instead is brain circuit-specific demonstrating increased phasic and tonic inhibition in the dentate gyrus with no comparative changes to inhibition in CA1 and medial prefrontal cortex. In the dentate, elevated extrasynaptic GABA signalling, and interneuron numbers, likely underpin spike firing defects. We show that increased GABA inhibition is caused by increased dosage of Olig1, Olig2 and Dyrk1a. Overall, DS mice are characterised by circuit-specific dysfunctional inhibition predicted to affect cognition via sparse coding in the hippocampus.

neuroscience↗

bioRxiv2025

Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome

Down syndrome, caused by trisomy 21, affects around six million people worldwide and features learning, memory and language deficits. However, the mechanisms underlying trisomy 21 neurophenotypes involving human cortical circuitry are unknown. By characterising developing neural network dynamics and single cell excitability profiles, with synaptic and voltage-dependent ion channel behaviour, using an isogenic induced pluripotent stem cell- derived neuronal model, we show that trisomy 21 impairs the activity and development of cortical circuitry. This is caused by deficient glutamatergic synaptic connectivity and by aberrant intrinsic membrane properties involving K+ and Na+ channels culminating in spike firing defects that weaken neural network activity and disrupt the synchrony of developing neurons. We also identify transiently activated A-type K+ channels, specifically Kv4.3 channels, as a key orchestrator for Down syndrome during neurodevelopment. Overall, these excitability changes will significantly contribute towards the aberrant neurophenotypes observed later on in life.

neuroscience↗

bioRxiv2024

A retrograde transit filter mediated by optineurin controls mitostasis in distal axons

The mechanisms of mitochondrial homeostasis in neurons-- mitostasis--are enigmatic and disease-prone, given a neurons large synaptic pool of mitochondria. To better understand mitostasis in mature mouse motor axons, we used ex vivo optical pulse-chase measurements of mitochondrial volume flux and identified a reiterative degradation system near presynaptic terminals and distal paranodes, which accounts for 75% of mitochondrial turnover in synapses. This distal filter system captures dysfunctional mitochondria from the retrograde stream and redirects them for lysosomal degradation. It depends on optineurin, a motor neuron disease-related mitophagy adaptor, but not on PINK1 and parkin, implicating a non-canonical mitophagy pathway. In presymptomatic motor neuron disease models, where retrograde transport is disrupted, the fraction of removed mitochondria is increased. Thus, we identify a new mitostasis system in distal axons with a cascade of checkpoints for local mitophagy, which normally maintains mitochondrial mass balance but is disrupted early in degenerative axonopathies.

cell biology↗

bioRxiv2020

Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5/mortalin in Drosophila

We investigate in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5/mortalin is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we study an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displays ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of DJ-1b, LRRK, p50, p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the autophagy machinery or overexpression of human mortalin broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.

genetics↗