Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1-/- mice.

Diana Matheoud, Tyler Cannon, Aurore Voisin, Anna-Maija Penttinen, Lauriane Ramet, Ahmed M. Fahmy, Charles Ducrot, Annie Laplante, Marie-Josée Bourque, Lei Zhu, Romain Cayrol, Armelle Le Campion, Heidi M. McBride, Samantha Gruenheid, Louis-Eric Trudeau, Michel Desjardins
Nature. 2019-07-01; 571(7766): 565-569
DOI: 10.1038/s41586-019-1405-y

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Matheoud D(1)(2), Cannon T(3), Voisin A(4), Penttinen AM(4), Ramet L(4), Fahmy AM(1), Ducrot C(4), Laplante A(1), Bourque MJ(4), Zhu L(3), Cayrol R(1), Le Campion A(5), McBride HM(6), Gruenheid S(7), Trudeau LE(8), Desjardins M(9).

Author information:
(1)Département de Pathologie et Biologie Cellulaire, Faculté de Médecine,
Université de Montréal, Montréal, Quebec, Canada.
(2)Département de Neurosciences, CRCHUM, Université de Montréal, Montréal,
Quebec, Canada.
(3)Department of Microbiology and Immunology, McGill University, Montreal,
Quebec, Canada.
(4)Département de Pharmacologie et Physiologie, Département de Neurosciences,
GRSNC, Faculté de Medecine, Université de Montréal, Montréal, Quebec, Canada.
(5)Département de Microbiologie, Immunologie et Infectiologie, Université de
Montréal, Montréal, Quebec, Canada.
(6)Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
.
(7)Department of Microbiology and Immunology, McGill University, Montreal,
Quebec, Canada. .
(8)Département de Pharmacologie et Physiologie, Département de Neurosciences,
GRSNC, Faculté de Medecine, Université de Montréal, Montréal, Quebec, Canada.
.
(9)Département de Pathologie et Biologie Cellulaire, Faculté de Médecine,
Université de Montréal, Montréal, Quebec, Canada. .

Comment in
Nature. 2019 Jul;571(7766):481-482.

Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to
the loss of dopaminergic neurons in the substantia nigra compacta. Although the
mechanisms that trigger the loss of dopaminergic neurons are unclear,
mitochondrial dysfunction and inflammation are thought to have key roles1,2. An
early-onset form of Parkinson’s disease is associated with mutations in the PINK1
kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are
involved in the clearance of damaged mitochondria in cultured cells4, but recent
evidence obtained using knockout and knockin mouse models have led to
contradictory results regarding the contributions of PINK1 and Parkin to
mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a
key role in adaptive immunity by repressing presentation of mitochondrial
antigens9, which suggests that autoimmune mechanisms participate in the aetiology
of Parkinson’s disease. Here we show that intestinal infection with Gram-negative
bacteria in Pink1-/- mice engages mitochondrial antigen presentation and
autoimmune mechanisms that elicit the establishment of cytotoxic
mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably,
these mice show a sharp decrease in the density of dopaminergic axonal
varicosities in the striatum and are affected by motor impairment that is
reversed after treatment with L-DOPA. These data support the idea that PINK1 is a
repressor of the immune system, and provide a pathophysiological model in which
intestinal infection acts as a triggering event in Parkinson’s disease,
which highlights the relevance of the gut-brain axis in the disease10.

 

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