Molecular signatures of altered energy metabolism and circadian rhythm perturbations in a model of synucleinopathy

A pathological role of alpha-synuclein (AS) aggregation in the nervous system is a recognized feature in Parkinson disease (PD) and related neurodegenerative conditions termed synucleinopathies. In order to characterize the cellular response in CNS to incipient and advanced AS aggregation, we applied spatial transcriptomics on brain sections derived from a mouse model at prodromal and symptomatic stages of pathology. Our spatially-resolved data point to unique perturbations in brain energy metabolism during the progression of AS pathology, such that there is an initial phase of hypermetabolism in disease-affected regions, which is followed by a profound decline leading to the symptomatic phase. This latter stage was also associated with drastic reduction in mRNA translation machinery, neuroinflammation and aberrant expression of molecular drivers controlling circadian rhythms. Collectively, these data offer novel opportunities in knowledge translation for mechanism-based drug discovery and potentially inform on biological markers reflecting disease progression in PD and related diseases. Overall design: Transgenic M83 mice overexpressing human mutant A53T AS (Prnp-SNCA*A53T) were bilaterally injected with pre-fibrillar aggregates of murine AS. Control animals were injected with phosphate-buffered saline (PBS, n=2) as control. Brains were collected at Early-stage pathology (Day 45, n=3) and Symptomatic stage (Day 75, n=3)