Choi HMC, Li Y, Suraj D, Hsia RC, Sarkar C, Wu J* and Lipinski MM*. Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury. PNAS. 2022; e2203824119. PMID: 36375051
Postdoctoral fellow Harry Choi collaborated with the Wu lab to demonstrate that after SCI autopahgy is initiated in the axons of injured neurons and promotes axonal degeneration. This function is mediated by the interaction of autopahgy regulator protein ULK1 and SARM1 NADase involved in axonal degeneration. ULK1-SARM1 complex formation promotes localization and activity of SARM1 in the injured axons. This is in contract to the pro-survival role of autopahagy in neuronal cell bodies.
Hegdekar N, Sarkar C, Bustos S, Ritzel RM, Hanscom M, Ravishankar P, Loane DJ, Wu J and Lipinski MM. Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes. Autophagy. 2023; Jan 18:1-19. PMID: 36652438
Graduate student Niv Hegdekar investigated the role of autopahgy in regulation of neuroinflammation after brain trauma. She used mice with a cell-type specific knock-out of the autoaphgy gene Becn1 in macrophgaes and microglia to demonstrate that inhibition of autopahgy after TBI leads to exacerbation of innate immune responses. This causeso overall increase in inflammation and contributes to poor connitive outcomes after injury.
Sarkar C, Jones JW, Hegdekar N, Thayer JA, Kumar A, Faden AI, Kane MA and Lipinski MM. PLA2G4A/cPLA2 mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma. Autophagy. 2020; 16(3):466-485. PMID: 31238788
Chinmoy Sarkar collaborated with the Kane and Jones labs at the UM School of Pharmacy to analyse changes in lysosomal lipid composition after TBI. Their data demonstrated that lysosomal membrane is permabilized after TBI by phospholipase cPLA2, leading to inhibition of autopahgy and neuronal cell death. Inhibition of cPLA2 can decrease lysosomla dysfunction and improve autopahgy in vitro and improve TBI recovery in vivo.
Thayer JA, Awad O, Hegdekar N, Sarkar C, Tesfay H, Burt C, Feldman RA and Lipinski MM. The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability. Autophagy. 2020;16(1):140-152. PMID: 30957634
Graduate student Julia Thayer identified USP24, a ubiquitin peptidase located in the PARK10 locus associated with Parkinson's disease, as a novel negative regulator of autophagy. USP24 knock-down promotes protein stability of the ULK1 kinase to increase initiation of autophagy. Decreasing levels of USP24 can also help protect neurite integrity in aged human iPSC derived dopaminergic neurons.