Transcriptional changes in the peripheral blood of at-risk individuals without clinical manifestation of Parkinson’s Disease

We have previously reported a global reduction of circular RNA (circRNA) levels in the peripheral blood of patients with early-stage idiopathic PD (iPD). This reduction was accompanied by increased expression of genes involved in innate immune response to double-stranded RNA. (dsRNA-IIR). Here, we extend these findings using whole-blood RNA sequencing data from 916 participants in the Parkinson’s Progression Markers Initiative. These consisted of individuals with idiopathic PD, pathogenic mutations in LRRK2 and GBA1, with and without disease manifestation, prodromal individuals with REM sleep behaviour disorder or hyposmia, two clinical features considered to indicate increased PD risk and healthy controls. We demonstrate that reduced circRNA abundance is not restricted to iPD but is also present in LRRK2 and GBA1-associated PD and in mutation carriers without manifest disease. CircRNA reduction was accompanied by increased expression of class I and class II transposable elements (TEs) and upregulation of dsRNA sensing and interferon-responsive genes, (ADAR1, DDX58/RIG-I, EIF2AK2/PKR and RNASEL. Inferred transcription factor activity was consistent with activation of antiviral and stress-signalling pathways. Among the prodromal groups, only individuals with hyposmia showed circRNA reduction, not those with REM sleep behaviour disorder, although, both groups exhibited elevated TE expression and increased expression of the genes mentioned above. Our results indicate that changes in circRNA levels are a general feature of PD and that their onset occurs early during disease development. They are consistent with dsRNA-IIR involvement in the in the development of PD and point to potential approaches for intervention.