Biology subjects

Hull, A.

Publications and source records attributed to Hull, A..

4 recordsLinked to original sources

bioRxiv2026

An overlooked distal regulatory signal on a shared haplotype drives the neuroinflammatory cascade underlying GBA1-associated Parkinson's disease

BACKGROUNDThe persistent puzzle of how GBA1 coding variants underlying monogenic Gaucher disease confer such strong risk for polygenic Parkinsons disease (PD) remains unresolved. Here, we sought to resolve this long-standing paradox. METHODSUsing the Parkinsons Progression Markers Initiative resource, we integrated whole-genome sequencing from sporadic PD cases and controls with matched transcriptomic, epigenomic and cerebrospinal fluid proteomic data across Northern European and Ashkenazi Jewish populations. Ancestry-specific genetic maps enabled precise integration of disease localisation with eQTL, pQTL and chromatin architecture, linking genetic association to molecular mechanism, while evolutionary genetic analyses resolved the regional haplotypic architecture. RESULTSWe identified a PD-associated regulatory signal located 150 kilobases distal to GBA1 that robustly replicated across all molecular datasets and both ancestries. Integrative mapping identified rs77268551-G as the candidate regulatory variant, which we show resides on an extended haplotype also carrying the Gaucher disease-causing N370S allele. Evolutionary analyses reveal a clear signature of recent positive selection acting on the Gaucher disease-causing N370S allele, giving rise to this extended shared haplotype that likely concealed the underlying distal PD-associated regulatory signal. rs77268551-G resides within a neuronal enhancer with features consistent with super-enhancer activity that orchestrates hierarchical enhancer-to-enhancer-to-promoter interactions with eleven cis-target genes, including ADAR, IL6R and GBA1, driving a coordinated transcriptional programme. Proteomic profiling identified genotype-specific cerebrospinal fluid protein signatures, including PARK7, BIN1 and SAA1, consistent with a neuroinflammatory programme. CONCLUSIONSThe findings support a dual-hit model in which a distal regulatory element is the primary driver of PD-associated molecular programmes, while co-inherited GBA1 protein-coding variation on the same haplotype modifies and amplifies the risk established by the regulatory variant, giving rise to the clinically distinct GBA1-associated PD phenotype. Regulatory activation and GBA1-related functional effects converge on neuroinflammatory and lysosomal pathways, and the resulting molecular signatures suggest genotype-linked biomarkers with potential clinical relevance.

genetics↗

bioRxiv2024

Smpd1 regulates chitin-clearance for tracheal gas-filling in the Drosophila embryo in a ceramide-specific manner

Type A and B Niemann Pick (NPD) is an inherited multisystem lysosomal storage disorder caused by mutations in the SMPD1 gene. Respiratory dysfunction is a key hallmark of NPD, although the precise mechanisms underlying these pathologies is underexplored. Here we present a Drosophila model of Smpd1 loss-of-function that displays significant respiratory defects. Smpd1 is expressed in the late-embryonic fly respiratory network, the trachea, and is secreted into the tracheal lumen. Loss of Smpd1 results in embryonic lethality, and although tracheal morphology appears normal, trachea fail to fill with gas prior to eclosion. We demonstrate that clearance of luminal constituents through endocytosis prior to gas-filling is defective in Smpd1 mutants. This is coincident with autophagic, but not lysosomal defects. Finally, we show that although bulk sphingolipids are unchanged, dietary loss of lipids in combination with genetic and pharmacological block of ceramide synthesis is sufficient to rescue gas-filling defects. In summary, we present a novel NPD model amenable to genetic and pharmacological screens, and highlight myriocin, an inhibitor of ceramide synthesis, as a potential therapeutic drug for the treatment of NPD.

genetics↗

bioRxiv2023

Quantifying myelin density in the feline auditory cortex

The cerebral cortex comprises many distinct regions that differ in structure, function, and patterns of connectivity. Current approaches to parcellating these regions often take advantage of functional neuroimaging approaches that can identify regions involved in a particular process with reasonable spatial resolution. However neuroanatomical biomarkers are also very useful in identifying distinct cortical regions either in addition to, or in place of functional measures. For example, differences in myelin density are thought to relate to functional differences between regions, are sensitive to individual patterns of experience, and have been shown to vary across functional hierarchies in a predictable manner. Accordingly, the current study provides quantitative stereological estimates of myelin density for each of the 13 regions that make up the feline auditory cortex. We demonstrate that significant differences can be observed between auditory cortical regions, with the highest myelin density observed in the regions that comprise the auditory core (i.e., the primary auditory cortex and anterior auditory field). Moreover, our myeloarchitectonic map suggests that myelin density varies in a hierarchical fashion that conforms to the traditional model of spatial organization in auditory cortex. Taken together, these results establish myelin as a useful biomarker for parcellating auditory cortical regions, and provide detailed estimates against which other, less invasive methods of quantifying cortical myelination may be compared.

neuroscience↗

bioRxiv2022

Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest genetic risk factor for Parkinsons disease (PD). Communication between gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread innate immune up-regulation, including gut inflammation and brain glial activation. We also demonstrate gut dysfunction in flies lacking Gba1b, with increased intestinal transit time, gut barrier permeability and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, can partially ameliorate lifespan, locomotor and some neuropathological phenotypes. Lastly, direct stimulation of autophagy by rapamycin treatment achieves similar beneficial effects. Overall, our data reveal that the gut microbiome drives systemic immune activation in Gba1b knockout flies and that reducing innate immune response activation either by eliminating the microbiota or clearance of immunogens by autophagy may represent potential therapeutic avenues for GBA1-associated neurodegenerative disease.

neuroscience↗