Patrick Ejlerskov

Senior Scientist, Danish Dementia Research Centre

Title: Interferon-β-induced Down-regulation of TBC1D15 Alleviates Neurotoxic Protein Accumulation by Controlling Autophagy

Abstract: Accumulation of neurotoxic protein aggregates is detrimental for neuronal function and survival and is associated with neurodegenerative proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neurotoxic protein aggregates can be degraded by autophagy, thus appropriate regulation of autophagy is crucial for neuronal homeostasis. Previously, we have shown that lack of the interferon-β gene, a crucial cytokine in the anti-viral innate immune defense, causes Parkinson-like pathology. We found that interferon-β activates autophagy and lack of this input causes a late-stage block in the autophagy pathway and consequently accumulation of neurotoxic proteins. Here, we report that interferon-β regulates autophagy via the microRNA miR-1, which targets the Tre-2/Bub2/CDC16 (TBC) Rab GTPase-activating protein, TBC1D15. Furthermore, reducing TBC1D15 in an in vivo model of PD alleviates α-synuclein induced neurotoxicity and behavioral defects. Hence, this work provides new mechanistic insight into how interferon-β regulates autophagy and proposes, that dysregulation of the anti-viral immune system or viral infections can be initiating factors for neurodegenerative diseases.