Biology subjects

Saez-Atienzar, S.

Publications and source records attributed to Saez-Atienzar, S..

7 recordsLinked to original sources

bioRxiv2026

Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia

Genome-wide association studies (GWAS) have identified many loci that contribute to the risk of neurodegenerative diseases. However, a persistent challenge in interpretation of GWAS is to break loci down to specific genes, variants, and cell types, and thus nominate disease mechanisms. Here, we used iPSC-derived cells containing population-level variation to examine GWAS loci across NDDs including Alzheimer's disease, Parkinson's disease and Lewy body dementia. We differentiated a set of 135 iPSC donor lines into two cell types relevant to neurodegeneration, neurons and microglia, and completed single cell gene expression and chromatin accessibility profiling. Meta-analysis of these data with published human brain snRNAseq for QTL mapping identified multiple loci associated with NDDs that are restricted to either neurons or microglia. Colocalization of GWAS and these QTL supports microglia as having a strong contribution to disease risk. We tested peaks nominated at the BIN1 locus for enhancer activity using a perturb-seq-based method in microglia. Our results show one of the nominated peaks controls BIN1 expression in microglia but also modifies expression of other genes at the locus. These results support the hypothesis that common variants affecting gene expression specifically in microglia can contribute directly to NDD risk rather than functioning solely as a secondary response to neurodegeneration. These data also show that iPSC-derived cells are a useful model to experimentally dissect GWAS loci that colocalize with QTL.

genomics↗

bioRxiv2024

Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/627515v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@18cda69org.highwire.dtl.DTLVardef@574c4corg.highwire.dtl.DTLVardef@1522644org.highwire.dtl.DTLVardef@4e799c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG HighlightsO_LIGeneration of a population-level set of iPSC lines from healthy individuals across the lifespan C_LIO_LIAging-related features were reset based on epigenetic markers of cytosine methylation and telomere length C_LIO_LIBy comparing methQTLs in iPSC vs. their donor PBMCs, we find that detection of methQTLs reflect biological functions of different cell types C_LI DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if aging-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to convert to iPSCs. After reprogramming we evaluated the resulting iPSCs for DNA methylation signatures to determine if they reflect the confounding factors of age and environmental factors. We used genome-wide DNA methylation arrays in both cell types to show that the epigenetic clock is largely reset to an early methylation age after conversion of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS). Finally, we identified a set of methylation Quantitative Trait Loci (methQTL) in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are genetically influenced.

molecular biology↗

bioRxiv2020

Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic cortical interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated five differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

genetics↗

bioRxiv2020

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Competing Interest StatementThomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.View Full Text

genomics↗

bioRxiv2020

Large-scale pathway-specific polygenic risk, transcriptomic community networks and functional inferences in Parkinson disease

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological pathways underlying PD using the largest currently available cohorts of genetic data and gene expression data from International Parkinsons Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership - Parkinsons disease initiative (AMP-PD), among other sources. We placed these insights into a cellular context. We applied large-scale pathway-specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk in a cohort of 457,110 individuals by focusing on a compilation of 2,199 publicly annotated gene sets representative of curated pathways, of which we nominate 46 pathways associated with PD risk. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data, including 4,331 individuals. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for adult dopaminergic neurons, serotonergic neurons, and radial glia. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of 1,612 PD patients, which revealed 54 connecting networks associated with PD. Our analyses highlight several promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

genetics↗

bioRxiv2020

LRRK2 mediates tubulation and vesicle sorting from membrane damaged lysosomes

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are a cause of familial and sporadic Parkinsons disease (PD). Nonetheless, the biological functions of LRRK2 remain incompletely understood. Here, we observed that LRRK2 is recruited to lysosomes that have a ruptured membrane. Using unbiased proteomics, we observed that LRRK2 is able to recruit the motor adaptor protein JIP4 to permeabilized lysosomes in a kinase-dependent manner through the phosphorylation of RAB35 and RAB10. Super-resolution live cell imaging microscopy and FIB-SEM revealed that once at the lysosomal membrane, JIP4 promotes the formation of LAMP1-negative lysosomal tubules that release membranous content from ruptured lysosomes. Released vesicular structures are able to interact with other lysosomes. Thus, we described a new process that uses lysosomal tubulation to release vesicular structures from permeabilized lysosomes. LRRK2 orchestrates this process that we name LYTL (LYsosomal Tubulation/sorting driven by LRRK2) that, given the central role of the lysosome in PD, is likely to be disease relevant.

cell biology↗

bioRxiv2019

Mutations in Auxilin cause parkinsonism via impaired clathrin-mediated trafficking at the Golgi apparatus and synapse

Parkinsons disease (PD) is a common neurodegenerative motor disorder characterized in part by neuropathological lesions in the nigrostriatal pathway. Loss of function mutations in Auxilin, the major neuronal clathrin uncoating protein, cause an aggressive form of juvenile onset PD. How mutations in Auxilin cause PD, is currently not understood. Here, we generated a novel mouse model carrying an endogenous pathogenic Auxilin mutation that phenocopies neurological features observed in patients, including motor impairments and seizures. Unbiased mapping of the Auxilin interactome identified synaptic and Golgi-resident clathrin adaptor proteins as novel interactors. Impaired clathrin-mediated trafficking in mutant Auxilin mice, both at the Golgi and the synapse, results in neuropathological lesions in the nigrostriatal pathway. Collectively, these results provide molecular mechanisms of PD pathogenesis in Auxilin mutation carriers, reinforcing a key role for clathrin-mediated trafficking in PD, and expand our understanding of the cellular function of Auxilin.

neuroscience↗