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Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopaminergic neurons (DNs). While it affects close to 3% of the population over 75 years of age, a significant proportion of PD patients — possibly as high as 10% — develops the disease due to familial, transmitted mutations, at a much earlier age. Two of the genes mutated in early-onset PD, PINK1 and Parkin, are involved in mitophagy, the process by which damaged mitochondria are captured for recycling within autophagosomes. Hence, it is assumed that in the absence of PINK1 or Parkin, failure to eliminate non-functional mitochondria in DNs results in the accumulation of toxic organelles, excessive oxidative stress and cell death. Although compelling, this model has proven difficult to validate in vivo as there is, so far, little evidence for a deregulation of mitophagy within DNs in PD. Furthermore, Parkin- and PINK1-independent pathways of mitophagy exist, suggesting the involvement of these proteins in PD through different mechanisms. Importantly, PINK1 and Parkin KO mice are generally healthy and display no signs of the disease. We have shown recently that PINK1 and Parkin play a role in the immune system by inhibiting the formation of mitochondria-derived vesicles (MDVs) and mitochondrial antigen presentation, a process we refer to as MitAP. In the absence of PINK1/Parkin, stress conditions such as inflammation induced by LPS treatment activate MitAP in antigen presenting cells (macrophages and dendritic cells) in vivo, a process leading to the establishment of autoreactive CD8+ T cells. LPS being the major component of the outer membrane of Gram-negative bacteria, we went on to show that gut infection with enteropathogenic E. coli (EPEC) induces MitAP and the elicitation of anti-mirochondrial CD8+ T cells in PINK1 KO mice. Remarkably, these animals display severe motor impairment as early as 3 months after infection, reversible by L-DOPA treatment. The link between infection, autoimmune mechanisms and the emergence of parkinsonism in PD-susceptible mice opens novel avenues for the development of therapeutics.
Michel Desjardins, Ph.D.
University of Montreal
12:00 pm at Van Andel Institute
Conference Room 2101/2102
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