Targeting CDC42 with CASIN Reprograms Cell Type Specific Transcriptomes and MAPK Driven Transcription Factor Networks in the Aging Brain

<jats:p>Background Parkinson disease (PD) is driven by alpha synuclein (alpha syn) aggregation and affects vulnerable dopaminergic and GABAergic neurons, and its incidence rises dramatically with age. In our alpha syn mouse model, motor impairment required both alpha syn oligomers and the aging milieu, and pharmacological inhibition of the age hyperactivated Rho GTPase CDC42 with CASIN fully restored motor function, yet the underlying transcriptional pathways mediating this rescue remain to be elucidated. Methods We used an inducible alpha syn oligomer PD mouse model across three age groups (6, 16, and 24 months) with four conditions per group: alhpa syn non-induced (OFF), induced (ON), and each with CASIN treatment (OFF CASIN, ON CASIN). Brain tissue from one hemisphere (0 to minus 5 mm Bregma) was sequenced using 10x Genomics 3' Chromium, with 3 to 4 mice per condition of both male and female mice. Results snRNA-seq demonstrated that CASIN robustly reverted PD related transcriptional alterations at 24 months whereas aging related changes were strongest at 16 months. Network and pathway analyses identified CASIN's mode of action on two major downstream signaling cascades, MAPK and PI3K/AKT, in the context of aging and MAPK signaling in PD. Conclusion Convergent gene, transcription factor, pathway, and network level evidence points to EGFR, PI3K, MAPK signaling as the axis through which CASIN may restore mitochondrial and synaptic function in PD and aging</jats:p>