Biology subjects

Kelly, K.

Publications and source records attributed to Kelly, K..

At least 19 recordsLinked to original sources

bioRxiv2026

The ortholog of the Human T2D Risk Gene STEAP2 is Required for Glucose Stimulated Insulin Secretion in Mice

Type 2 diabetes is a complex metabolic disease with a strong genetic component, yet this genetic risk is driven by common variants in up to 600 loci with small effect sizes. Variants in the STEAP2 locus, encoding Six-transmembrane epithelial antigen of the prostate-2, are highly associated with altered glycemic traits and type 2 diabetes risk. To elucidate its function in pancreatic beta-cells, we utilized Crisp-Cas9 assisted homologous recombination to derive a conditional null allele for Steap2 (Steap2fl/fl) in mice and crossed this to the rat insulin promoter (Rip)-Cre transgene. Ablation of Steap2 induced glucose intolerance, blunted glucose-stimulated Ca2+ mobilization and stunted first phase glucose-simulated insulin secretion. In contrast, the incretin effect and second phase insulin secretion were not affected. Islet respirometry and transmission electron microscopy (TEM) identified disrupted cristate morphology and impaired glucose-stimulated oxygen consumption as causally responsible for the observed, impaired triggering pathway of insulin secretion. These findings suggest that at least part of the genetic risk for T2D conferred by Steap2 variants is likely due to its function in maintaining optimal mitochondrial respiration in pancreatic beta-cells.

genetics↗

bioRxiv2026

Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma

Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

cancer biology↗

bioRxiv2026

A Novel Method for Across-Chromosome Phasing without Relative Data

MotivationAcross-chromosome phasing identifies which haplotypes of different chromosomes come from the same parent. This differs from within-chromosome phasing, which uses linkage disequilibrium patterns to determine which alleles were co-inherited within each chromosome but does not match haplotypes across different chromosomes. While across-chromosome phasing can be conducted using genotypes from parents or close relatives, current methods perform poorly for samples of unrelated individuals. Here, we introduce a novel approach for across-chromosome phasing that employs a window-based SNP-similarity metric, eliminating the need for data from close relatives or detection of identical-by-descent haplotypes. ResultsUsing UK Biobank offspring with both parents genotyped as a gold standard, we evaluated the performance of our method by phasing the offspring without using parental data. In genomic data with no within-chromosomal phase errors, our algorithm achieved a mean across-chromosome phasing accuracy of 95%, with 53% of individuals phased perfectly. When data was pre-phased computationally using a standard within-chromosomal phasing algorithm, mean accuracy for across-chromosome phasing dropped to 83.1%. Thus, our method is limited primarily by the accuracy of within-chromosome phasing, and can approach near perfect across-chromosome phasing accuracy as within-chromosome phasing accuracy improves. Contactemmanuel.sapin@colorado.edu and matthew.c.keller@colorado.edu

genomics↗

bioRxiv2026

Near perfect identification of half sibling versus niece/nephew avuncular pairs without pedigree information or genotyped relatives

Motivation: Large-scale genomic biobanks contain thousands of second-degree relatives with missing pedigree metadata. Accurately distinguishing half-sibling (HS) from niece/nephew-avuncular (N/A) pairs--both sharing approximately 25% of the genome--remains a significant challenge. Current SNP-based methods rely on Identical-By-Descent (IBD) segment counts and age differences, but substantial distributional overlap leads to high misclassification rates. There is a critical need for a scalable, genotype-only method that can resolve these "half-degree" ambiguities without requiring observed pedigrees or extensive relative information. Results: We present a novel computational framework that achieves near-complete separation of HS and N/A pairs using only genotype data. Our approach utilizes across-chromosome phasing to derive haplotype-level sharing features that summarize how IBD is distributed across parental homologues. By modeling these features with a Gaussian mixture model (GMM), we demonstrate near-perfect classification accuracy (> 98%) in biobank-scale data. Furthermore, we show that these high-confidence relationship labels can serve as long-range phasing anchors, providing structural constraints that improve the accuracy of across-chromosome homologue assignment. This method provides a robust, scalable solution for pedigree reconstruction and the control of cryptic relatedness in large-scale genomic studies.

bioinformatics↗

bioRxiv2025

Albumin-binding dendrimer-conjugated siRNA enables safe and effective gene silencing throughout the central nervous system

Improving siRNA delivery to the central nervous system (CNS) is a major focus for treating the numerous debilitating neurological conditions which have a genetic basis. Here, we present an albumin-binding siRNA based on an amphiphilic dendrimer conjugate (D-siRNA). We demonstrate that D-siRNA achieves effective and homogeneous delivery throughout the CNS following administration into the cerebrospinal fluid (CSF). In mice, a single CSF administration of D-siRNA resulted in potent and durable gene silencing across various brain regions, with effects lasting six months without detectable toxicity. We validate its utility in larger rodents (rats) using intrathecal administration--a clinically relevant route--showing effective and broad delivery and robust silencing. Benchmarking against other clinically relevant siRNA delivery scaffolds revealed that D-siRNA provides comparable delivery and efficacy, with more efficient conversion of gross uptake to functional uptake. These findings support the use of albumin-binding conjugates for brain delivery, and position D-siRNA as a safe, effective, and durable platform for gene silencing in the CNS.

pharmacology and toxicology↗

bioRxiv2025

GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer

Estrogen receptor alpha (ER)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling independently of estrogen. These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

cancer biology↗

bioRxiv2025

Basal forebrain volume is associated with cortical amyloid burden in cognitively unimpaired older adults at varying genetic risk for Alzheimers disease

BackgroundIn mild cognitive impairment and dementia due to Alzheimers disease (AD), postmortem and in vivo neuroimaging studies have demonstrated significant neuronal loss in the basal forebrain cholinergic system (BFCS), which provides the primary cholinergic input to the cerebral cortex. Within this region, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a group of posteriorly clustered magnocellular neurons in the BFCS. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in the preclinical stages of AD. The current study investigates the relationship between sub-structural BFCS volume and cortical A{beta} burden in cognitively unimpaired middle-aged individuals at varying genetic risk for AD. MethodsCognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype {varepsilon}4{varepsilon}4 (n=15), {varepsilon}3{varepsilon}4 (n=15), and {varepsilon}3{varepsilon}3 (n=15), matched for age and sex. Participants underwent imaging with [11C]PiB PET and structural 3T MRI. Distribution volumes ratios (DVR) with a whole cerebellum reference region were calculated for [11C]PiB PET analyses. BFCS sub-structural volumes were obtained from the SPM8 Anatomy Toolbox (Cholinergic nuclei [Ch] 1-3, Ch4). MTL subregional volumes (entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using Freesurfer. ResultsBFCS amyloid burden was highest among APOE {varepsilon}4 homozygotes (Ch1-3, F(2, 42)=3.26, P=0.048; Ch4, F(2, 42)=3.82, P= 0.03). Ch4 (nbM), but not Ch1-3 volume, was found to be inversely associated with global A{beta} burden (Pearson r=-0.40, P=0.007). MTL subregional volumes were not associated with global A{beta} burden in the pooled sample. Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (P=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson r = -0.70, P=0.02) in A{beta}+ participants. ConclusionsWe observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, A{beta}+, middle-aged adults at varying genetic risk for AD. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.

neuroscience↗

bioRxiv2025

Device encapsulated MSCs for adaptive secretome therapy to effectively target ischaemic heart injury

Effective long-term strategies to protect the ischaemic heart remain a significant challenge. Mesenchymal stem cells (MSCs) offer therapeutic potential primarily through their secretome, a bioactive factor-rich milieu with broad beneficial effects. However, existing delivery methods have not been shown to provide sustained benefits. Herein, we introduce an innovative approach for sustained MSC-secretome delivery for long-term cardioprotection. In a rat model of chronic myocardial infarction, Cymerus MSCs, derived from human induced pluripotent stem cells (iPSCs), were encapsulated in a Procyon immunoisolation device and implanted subcutaneously. A human-iPSC-derived engineered cardiac microtissue model was used to simulate ischaemia-reperfusion injury and assess cardioprotective effects in a human context. The MSC-loaded Procyon device significantly improved cardiac function and reduced adverse left ventricular remodelling over a 12-week period. These positive effects were consistent across both young and middle-aged, male and female rats, indicating broad applicability. The encapsulated MSCs remained viable and continuously released therapeutic secretome for 12 weeks. In vitro, the MSC secretome protected human engineered cardiac microtissues from simulated ischaemia-reperfusion injury, restoring contractile function, improving cell viability, and reducing oxidative stress. Proteomic analysis of MSCs revealed 179 unique cellular proteins post-implantation, linked to adaptive immune and inflammatory responses as well as wound healing. MSC secretome profiling revealed increased protein diversity associated with tissue repair and immune regulation, suggesting MSCs undergo an adaptive response to ischaemic conditions, enhancing their therapeutic potential. This translational study highlights a clinically viable, minimally invasive method for sustained cardioprotection, harnessing the MSC secretome to address a pivotal gap in current treatments for ischaemic heart disease.

pathology↗

bioRxiv2024

Acute Myeloid Leukemia with deletion 5q is an epigenetically distinct subgroup defined by heterozygous loss of KDM3B

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a block in differentiation and accelerated proliferation of myeloid progenitor cells. Genes encoding for epigenetic regulators are among the most frequent targets for mutations and structural variations in AML, giving rise to profound epigenetic heterogeneity between and within tumors. Deletions of chromosome 5q [del(5q)] are among the most common copy number alterations in AML and are associated with extremely poor clinical outcome and therapy resistance, however the mechanisms linking del(5q) to leukemic progression are not understood. Analyzing DNA methylation profiles from 477 elderly AML patients using DNA methylome deconvolution, we discovered that del(5q) AML is an epigenetically distinct subgroup characterized by a signature of DNA hypermethylation, which we propose may be linked to dysregulation of H3K9me1/2 and overexpression of the leukemic stem cell marker, DNMT3B. Interrogation of the minimally deleted 5q region highlighted the H3K9me1/2 demethylase KDM3B as a likely target for haploinsufficiency in this subgroup. Our data suggest that del(5q) AML should be reconsidered as an epigenetically dysregulated subgroup, driven by heterozygous loss of KDM3B, and that the resulting imbalance of H3K9me1/2 may contribute to the progression of these aggressive leukemias.

cancer biology↗

bioRxiv2024

Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML. Statement of significanceThis study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.

cancer biology↗

bioRxiv2024

EpiCHAOS: a metric to quantify epigenomic heterogeneity in single-cell data

Epigenetic heterogeneity is a fundamental property of biological systems, and is recognized as a potential driver of tumor plasticity and therapy resistance. Single-cell epigenomics technologies have been widely employed to study epigenetic variation between - but not within - cellular clusters. We introduce epiCHAOS: a quantitative metric of cell-to-cell heterogeneity, applicable to any single-cell epigenomics data type. After validation in synthetic datasets, we applied epiCHAOS to investigate global and region-specific patterns of epigenetic heterogeneity across diverse biological systems. EpiCHAOS provides an excellent approximation of stemness and plasticity in development and malignancy, making it a valuable addition to single-cell cancer epigenomics analyses.

bioinformatics↗

bioRxiv2023

Metabolic and imaging phenotypes associated with RB1 loss in castrate resistant prostate cancer

Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.

cancer biology↗

bioRxiv2023

Addressing the dNTP bottleneck restricting prime editing activity

Prime editing efficiency is modest in cells that are quiescent or slowly proliferating where intracellular dNTP levels are tightly regulated. MMLV-reverse transcriptase - the prime editor polymerase subunit - requires high intracellular dNTPs levels for efficient polymerization. We report that prime editing efficiency in primary cells and in vivo is increased by mutations that enhance the enzymatic properties of MMLV-reverse transcriptase and can be further complemented by targeting SAMHD1 for degradation.

biochemistry↗

bioRxiv2023

Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with [~]20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1G85R protein expression. Heterozygous Sod1G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival. SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.

neuroscience↗

bioRxiv2023

Engineering Nme2Cas9 Adenine Base Editors with Improved Activity and Targeting Scope

Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we have engineered Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first used domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibited shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expanded the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We used these enhancements to correct two common MECP2 mutations associated with Rett syndrome with little or no bystander editing. Finally, we validated domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.

molecular biology↗

bioRxiv2023

Self-delivering CRISPR RNAs for AAV Co-delivery and Genome Editing in vivo

Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges for delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a "protecting oligo"), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNA in vivo. Finally, we achieved in vivo genome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation.

molecular biology↗

bioRxiv2023

Eelgrass (Zostera spp.) associated phytomyxids are host-specific congeneric parasites and predominant eukaryotes in the eelgrass rhizosphere on a global scale

Together with increasing environmental and anthropogenic pressures, pathogenic diseases are one of important factors contributing to the ongoing decline of seagrass meadows worldwide; yet the diversity and ecology of the microorganisms acknowledged as seagrass parasites remain critically understudied. Here we investigate phytomyxid parasites (Rhizaria: Endomyxa: Phytomyxea) of three different eelgrass (Zostera spp.) species found in the Northern hemisphere. We present molecular evidence that Plasmodiophora bicaudata, a long-recognized parasite of dwarf eelgrass taxa, is closely related to the novel phytomyxid recently discovered in root hairs of Zostera marina, and together they form a distinct clade within the order Phagomyxida, proposed here as Feldmanniella gen. nov. A full life cycle is systematically described in a phagomyxid representative for the first time, proving its conformity with the generalized phytomyxid life history, despite previous uncertainties. The presence of primary infection stages in nearly all collected eelgrass specimens, and subsequent analysis of amplicon sequences from a global Z. marina dataset, reveal phytomyxids to be ubiquitous and one of the predominant microeukaryotes associated with eelgrass roots on a global scale. Our discoveries challenge the current view of Phytomyxea as rare entities in seagrass meadows and suggest their generally low pathogenicity in natural ecosystems. Originality-Significance StatementThis study addresses a group of microbial parasites critically understudied in the marine environment. It presents complex evidence that Phytomyxea - obligate intracellular biotrophs previously considered to be rare entities in the oceans, are in fact ubiquitous endobionts of seagrasses of the genus Zostera - foundation species and important primary producers in coastal areas worldwide. Our work represents a significant contribution to the fields of aquatic microbiology and seagrass ecology and is seminal to understanding the biology of Phytomyxea outside of terrestrial ecosystems.

microbiology↗

bioRxiv2023

Protein network analysis links the NSL complex to Parkinson's disease and mitochondrial biology

Whilst the majority of PD cases are sporadic, much of our understanding of the pathophysiological basis of disease can be traced back to the study of rare, monogenic forms of disease. In the past decade, the availability of Genome-Wide Association Studies (GWAS) has facilitated a shift in focus, toward identifying common risk variants conferring increased risk of developing PD across the population. A recent mitophagy screening assay of GWAS candidates has functionally implicated the non-specific lethal (NSL) complex in the regulation of PINK1-mitophagy. Here, a bioinformatics approach has been taken to investigate the proteome of the NSL complex, to unpick its relevance to PD progression. The mitochondrial NSL interactome has been built, mining 3 separate repositories: PINOT, HIPPIE and MIST, for curated, literature-derived protein-protein interaction (PPI) data. We built; i) the mitochondrial interactome, applying gene-set enrichment analysis (GSEA) to explore the relevance of the NSL mitochondrial interactome to PD and, ii) the PD-oriented interactome to uncover biological pathways underpinning the NSL /PD association. In this study, we find the mitochondrial NSL interactome to be significantly enriched for the protein products of PD associated genes, including the Mendelian PD genes LRRK2 and VPS35. Additionally, the PD associated interactome is enriched for mitochondrial processes; "mitochondrial cell death", "mitochondrial protein localisation", "membrane protein localisation" and "mitochondrial transport". Our data points to NSL complex members OGT and WDR5 as key drivers of this increased PD association. These findings strengthen a role for mitochondrial quality control in both familial and sporadic disease.

neuroscience↗