Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson’s disease

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Abstract
Parkinson’s disease (PD) is a common age-related neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TE) have been linked to inflammatory states, but their potential role in PD has not been explored. Using bulk– and single nuclei RNAseq of postmortem brain tissue from four brain regions, we studied TE transcriptional activation and its correlation with neuroinflammation in PD. Over a thousand TE loci, including LINE-1s and ERVs, were highly expressed in a cell-type and region-specific manner in the human brain. Increased TE expression was found in microglia and neurons in the substantia nigra and putamen in the PD brains, but not amygdala or prefrontal cortex, compared to age-matched control tissue. This TE activation correlated with innate immune transcriptional responses, characterized by the expression of interferon-related and viral response genes, in the same brain regions. The link between an interferon response and TE activation was mechanistically confirmed using human pluripotent stem cell-derived microglia and neurons. Our findings provide a unique insight into TE transcription in the PD brain and suggests that TEs play a role in chronic neuroinflammatory processes and the progression of this neurodegenerative disorder.
Funding Information
  • Aligning Science Across Parkinson’s through the Michael J. Fox Foundation for Parkinson’s Research (ASAP-000520)
  • Aligning Science Across Parkinson’s through the Michael J. Fox Foundation for Parkinson’s Research (ASAP-024296)
  • Aligning Science Across Parkinson’s through the Michael J. Fox Foundation for Parkinson’s Research (ASAP-025170)
  • Swedish Government Initiative for Strategic Research Areas
  • Novo Nordisk Fonden (NNF21CC0073729)
  • Bioneer A/S (DigitStem grant)
  • NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
  • NIHR Cambridge Biomedical Research Centre (NIHR203312)

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