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SUMMARY:The Parkinson’s disease protein LRRK2 regulates the transition f
 rom innate to adaptive immunity by modulating the unfolded protein respons
 e - Professor Michel Desjardins\, University of Montreal
DTSTART:20221031T150000Z
DTEND:20221031T160000Z
UID:TALK183182@talks.cam.ac.uk
CONTACT:Hannah Burns
DESCRIPTION:Emerging evidence identify the immune system as a key player i
 n the pathophysiological process leading to Parkinson’s disease (PD). Wh
 ile it is widely accepted that innate immunity (inflammation) is a key fac
 tor in the disease\, the contribution of the second arm of the immune syst
 em\, adaptive immunity\, is still being questioned. We have shown previous
 ly\, both in vitro and in vivo\, that the PD proteins PINK1 and Parkin reg
 ulate the engagement of an adaptive immune response during inflammation. I
 ndeed\, in the absence of PINK1\, autoimmune mechanisms are initiated in i
 nflammatory conditions by the presentation of mitochondrial antigens (MitA
 P) at the surface of antigen-presenting cells. The presentation of these a
 ntigens\, which activates CD8+ T cells displaying a cytotoxic activity tow
 ards dopaminergic neurons\, leads to the development of motor impairment i
 n PINK1-/- mice after a gut infection with Gram-negative bacteria. These d
 ata led us to propose that autoimmune mechanisms play a key role in the pa
 thophysiological process leading to PD. Characterization of the molecular 
 mechanisms regulating MitAP revealed that the transition from innate (infl
 ammation) to adaptive immunity (antigen presentation) occurs through a com
 plex pathway where the Toll-like receptor 4\, cGAS-STING and the unfolded 
 protein response (UPR) are triggered sequentially. Remarkably\, we found t
 hat LRRK2 is required for the activation of the UPR in inflammatory condit
 ions. Failure to activate the UPR in RAW macrophages lacking LRRK2 results
  in a significant inhibition of MitAP.  Interestingly\, the UPR plays a ke
 y role in Crohn’s disease\, which is also linked to LRRK2 dysfunction. T
 hese data suggest that the UPR is a key step to target in order to limit t
 he engagement of autoimmune mechanisms that may contribute to PD.
LOCATION:MRC MBU\, Level 7 Lecture Theatre\, The Keith Peters Building\, C
 B2 0XY
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