Franklin, E. E. | Search bioRxiv

bioRxiv2026

Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinsons Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

neuroscience↗

bioRxiv2026

Ms4a4a loss reprograms amyloid-associated microglia and limits dense-core plaque-associated tau spreading

INTRODUCTIONMicroglia regulate amyloid plaque-associated microenvironments that contribute to downstream tau pathology in Alzheimers disease (AD). Variants within the MS4A locus are strongly associated with AD risk and resilience and are linked to microglial biology; however, the functional role of MS4A4A in plaque-associated tau pathology remains poorly understood. METHODSSingle-nucleus RNA sequencing (snRNA-seq) was performed on hippocampi from non-transgenic, Ms4a4a knockout (4A-KO), 5xFAD, and 5xFAD 4A-KO mice at 6 months of age. To assess plaque-associated tau pathology, AD-derived tau aggregates were injected into the hippocampus of 5xFAD and 5xFAD 4A-KO mice at 6 months, and histological analyses were performed 3 months later. RESULTSAmyloid pathology was the dominant driver of microglial state transitions, while Ms4a4a loss selectively remodeled activated microglial transcriptional programs enriched for interferon, lysosomal, autophagic, and proteostatic pathways. Activated microglia from 5xFAD 4A-KO mice exhibited altered expression of genes linked to immune signaling and protein handling. Following AD-tau inoculation, Ms4a4a loss did not significantly alter overall phospho-tau burden but selectively reduced dense-core plaque-associated neuritic plaque tau (NP-tau), particularly in the contralateral hemisphere. This phenotype was strongest surrounding X-34-positive fibrillar plaques and occurred without major changes in plaque-associated microgliosis. DISCUSSIONThese findings identify Ms4a4a as a regulator of plaque-associated microglial programs linked to NP-tau accumulation in the amyloid-bearing brain. More broadly, this work supports a model in which AD resilience-associated microglial pathways selectively shape plaque-associated microenvironments that promote downstream tau pathology.

neuroscience↗