Transcriptional Dysregulation in the Hippocampus of a murine model for Parkinson’s Disease Cognition Impairment is Driven by Sex, Age, and Alpha-synuclein overexpression

Abstract Cognitive impairment is the most common and detrimental, but understudied non-motor symptom of Parkinson’s disease (PD). Neuropathologically, it is associated with alpha-synuclein (αSyn) misfolding and synapse loss in hippocampus and prefrontal cortex, leading to cognition loss and ultimately dementia. The molecular underpinnings of PD-associated cognitive dysfunction are unknown. In the present study, longitudinal gene expression profiling was performed to characterise molecular hippocampal alterations in a transgenic mouse overexpressing E46K mutated αSyn, a model of early PD with loss of synaptophysin, a proxy marker of cognition, in hippocampus and cortex. Comparing 4 different ages of mice from both sexes showed that hippocampal gene expression changes were sexually dimorphic and strongly modulated by age and αSyn overexpression. Pathways that emerged across different comparisons were connected to a variety of neuronal functions, collagen synthesis/remodelling, cellular stress, and inflammatory responses. The findings indicate that sex and age are essential covariates to consider when studying PD-associated cognitive decline. The uncovering of early events leading to disease in an animal model is an essential step toward prognostic biomarker identification and early interventions, which may have implications for monitoring, and for timing of therapeutic approaches. Competing Interest Statement The authors have declared no competing interest. Abbreviations - 6-OHDA - 6-hydroxydopamine - αSyn - alpha-synuclein - APBA3 - Amyloid Beta Precursor Protein-Binding, Family A, Member 3 - APP - Amyloid Beta Precursor Protein - BAC - Bacterial artificial chromosome - BBB - Blood brain barrier - Brain-PAD - Brain-predicted age difference - CA1 - Cornu Ammonis 1 - CA3 - Cornu Ammonis 3 - CAS - Common age signature - CHRNA6 - Cholinergic Receptor, Nicotinic, Alpha Polypeptide 6 - CNS - Central nervous system - CREB - cAMP Response Element-Binding Protein - Ddx3x - DEAD-Box Helicase 3 X-Linked - DEGs - Differentially expressed genes - DLB - Dementia with Lewy bodies - DNA - Deoxyribonucleic acid - ECM - Extracellular matrix - GABA - Gamma-aminobutyric acid - GO - Gene ontology - GP6 - Glycoprotein VI Platelet - GSTM1 - Glutathione S-Transferase M1 - GTPases - guanosine triphosphate binding proteins - HET - Heterozygous - IPA - Ingenuity Pathway Analysis - Kdm5c - Lysine Demethylase 5C - Kdm5d - Lysine Demethylase 5D - log10p - logarithm base 10 of the p-value - MAPK - Mitogen-activated protein kinase - MCI - mild cognitive impairment - MPTP - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine - NMDA - N-methyl-D-aspartate - PCA - Principal component analysis - PD - Parkinson’s Disease - PDD - Parkinson’s Disease Dementia - RNA - Ribonucleic acid - RNAseq - RNA sequencing - RT-qPCR - Quantitative reverse transcription polymerase chain reaction - SNCA - alpha-synuclein, human - Snca - alpha-synuclein, mouse - Tg - transgenic - VPS35 - Vacuolar Protein Sorting 35 - WT - wild-type littermate - Xist - X-inactive specific transcript