Biology subjects

Sutherland, G.

Publications and source records attributed to Sutherland, G..

4 recordsLinked to original sources

bioRxiv2026

Quantitative Imaging and Characterization of Ganglioside Diversity in Mouse and Human Brain Tissues

Our understanding of how ganglioside species are spatially and quantitatively distributed within regions in mammalian remains limited. Studies are typically translated from rodents, assuming that gangliosides species contents within brain regions reflect the human condition. Herein, we provide a rich spatial ganglioside brain atlas describing the content, compositional differences, and concentrations of 48 ganglioside species across different regions in mouse and humans with no clinically known neurodegeneration. Our quantitative mass spectrometry imaging (MSI) approach allows non-rigid co-registration of mass spectrometry and microscopy images to allow precise spatial alignment and extraction of normalised ganglioside concentration data to reference mouse brain tissue anatomy and neuropathological annotated tissues for flexible downstream lipidomics analysis. Considerable differences and similarities are observed permitting region-specific ganglioside maps across twelve brain regions in wild type mouse. Gangliosides in mouse brain tissue generally preferred Cer 36:1;O2 configurations whereas human gangliosides in corresponding anatomically-annotated regions tended to favour Cer 38:1;O2 and longer backbones. Notably, this observation is more pronounced in gray matter compared to white matter. Collectively, this study defines the precise and quantitative ganglioside atlases across mice and human brains to guide and accelerate the discovery of biomarkers and therapeutic targets for brain diseases.

neuroscience↗

bioRxiv2024

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. We found that a significant portion of the alcohol-induced changes in gene expression occurred through altered chromatin accessibility. Notably, we identified novel transcriptional and chromatin accessibility differences in medium spiny neurons, impacting pathways such as RNA metabolism and immune response. A small cluster of D1/D2 hybrid neurons showed distinct differences, suggesting a unique role in AUD. Microglia exhibited distinct activation states deviating from classical M1/M2 designations, and astrocytes entered a reactive state partially regulated by JUND, affecting glutamatergic synapse pathways. Oligodendrocyte dysregulation, driven in part by OLIG2, was linked to demyelination and increased TGF-{beta}1 signaling from microglia and astrocytes. We also observed increased microglia-astrocyte communication via the IL-1{beta} pathway. Leveraging our multiomic data, we performed cell type-specific expression quantitative trait loci analysis, integrating that with public genome-wide association studies to identify AUD risk genes such as ADAL and PPP2R3C, providing a direct link between genetic variants, chromatin accessibility, and gene expression in AUD. These findings not only provide new insights into the genetic and cellular mechanisms in the caudate related to AUD but also demonstrate the broader utility of large-scale multiomic studies in uncovering complex gene regulation across diverse cell types, which has implications beyond the substance use field.

neuroscience↗

bioRxiv2024

Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease

Underlying drivers of late-onset Alzheimers disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed A{beta} localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal A{beta}. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with A{beta}1-42, and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of A{beta} in neuronal lysosomes to drive AD amyloid pathology. SummaryCellular and molecular drivers of late-onset Alzheimers disease (LOAD) are unknown, though several risk factors account for the majority of disease incidence1-5. Though diverse in their biological natures, each of these risk exposures converge on a shared pathological progression with the accumulation of amyloid early in the disease. Human genetic and transcriptomic studies suggest a role for altered lipid metabolism6-9, though the mechanism has been unknown. Here, using two common midlife risk exposures for LOAD, we found that dysfunctional lipophagy caused by the loss of lysosomal acid lipase (LAL) promotes early LOAD pathogenesis. Both midlife obesity and heavy alcohol reduced neuronal LAL, causing an increase in neuronal lysosomal lipid, and a subsequent accumulation of A{beta} in the extra-lysosomal cytosol. This loss of LAL preceded and promoted A{beta} pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented increases in amyloid and improved cognition. In human brain, LAL declined with age in healthy subjects, similar to rodents, showing robust losses in LOAD subjects with polymerase pausing. Together, this implicates neuronal LAL loss in LOAD pathogenesis and presents LAL as a promising diagnostic, preventative, and/or therapeutic target for AD.

neuroscience↗

bioRxiv2019

Accelerated loss of hypoxia response and biased allele expression in zebrafish with Alzheimer’s disease-like mutations

Ageing is the major risk factor for Alzheimers disease (AD), a condition involving brain hypoxia. The majority of early onset familial AD (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for AD occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfAD pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.

genomics↗