Molecular aging is the main driver of Parkinson’s Disease

Abstract Aging as well as the presence of α-synuclein (α-syn) oligomers in the brain are indisputably linked to Parkinson’s disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with α-syn oligomers for the onset of PD symptoms remains unclear. Using an inducible α-syn oligomer mouse model of PD, we demonstrate that the induction of PD associated α-syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that α-syn oligomer formation precedes motor decline in these aged mice, and age together with α-syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of α-syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the α-syn model of PD. Competing Interest Statement K. M. Danzer and H. Geiger are listed as inventors on a patent application related to this technology. The authors declare no further competing interests. Abbreviations - α-syn - α-synuclein - Adcy - adenylyl cyclase - ASC - astrocytes - AUC - area under the curve - BGNs - basal ganglia neurons - CASIN - CDC42 activity specific inhibitor - CDC42 - cell division control protein 42 homolog - CHOR - choroid plexus - CPS - counts per second - DaN - dopaminergic neurons - DEGs - differentially expressed genes - GEMs - gel beads-in-emulsion - Grm5 - glutamate metabotropic receptor 5 - M - month - MAR - missing at random - MassSpec - Mass Spectrometry - MGL - microglia - MNAR - missing not at random - nUMI - number of unique molecular identifiers - OLG - oligodendrocytes - OPC - oligodendrocyte progenitor cells - PCA - protein complementation assay - PD - Parkinson’s Disease - PDE - phosphodiesterase - PID - partial information decomposition - PKA - protein kinase A - SEC - Size-Exclusion Chromatography - snRNA-seq - single-nuclei RNA-sequencing - UMAP - Uniform Manifold Approximation and Projection algorithm - UPS - ubiquitin-proteasome system - Vo - void volume - VSC - vascular cells