27 Sep 2019

The LRRK2 variant, G2019S, increases a person’s chances of getting Parkinson’s disease, but may help protect against infection, according to research in the September 25 Science Translational Medicine. Scientists led by Michael Schlossmacher at the University of Ottawa, Canada, report that G2019S revved up the immune response in mice, improving survival from peripheral infections. In the brain, however, this response backfired, as immune cells released reactive oxygen species that exacerbated neurodegeneration and reduced survival. α-Synuclein in the brain also shot up, hinting that the combination of LRRK2 variant and environmental trigger might kick off Parkinson’s. Schlossmacher presented some of these data at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held in March 2018 in Turin, Italy (Apr 2018 conference news). 

Schlossmacher’s group investigated the immune effects of LRRK2 because the kinase is mostly expressed in macrophages, monocytes, and microglia, and very little in the dopaminergic neurons that are lost in PD (Mar 2013 conference news). In the current study, joint first authors Bojan Shutinoski and Mansoureh Hakimi examined postmortem human tissue and surgical biopsies to find robust LRRK2 expression in white blood cells that had infiltrated inflamed human brains, including brainstems infected with HIV and cortices harboring rabies virus. In PD brainstems, LRRK2 was mostly expressed by leukocytes inside blood vessels, not by neurons or glia.

To find out what LRRK2 does in immune cells, the authors turned to mice. They infected about 50 adult animals with Salmonella typhimurium, which causes lethal sepsis. Female, but not male, LRRK2 knockout mice struggled to fight off the infection, accumulating a fivefold higher bacterial load than did wild-types. The reason for this sex difference remains murky. All the mice died within three weeks of infection. Despite greater bacterial proliferation, female LRRK2 knockouts survived as long as did male knockouts and wild-type mice.

The G2019S variant had opposite, and more dramatic, effects than the knockouts. G2019S knock-in mice handily squelched the infection, with bacterial loads in both females and males reaching but a tenth and a fifth, respectively, of what they did in wild-type. Because the effect was stronger in females, the authors used them for subsequent analyses of Salmonella infection.

They found that the protective effect of G2019S against Salmonella depended on myeloid cells, since depletion of monocytes and neutrophils abolished it. In infected females, G2019S myeloid cells generated more reactive oxygen species in the spleen and brain than did those myeloid cells in wild-type mice. The net effect was to improve survival, with female G2019S heterozygotes and homozygotes living an additional seven and 12 days, respectively, after blood infection than did controls.

What would happen with a brain infection? The authors sprayed reovirus in the noses of about 200 newborn mouse pups. The virus rapidly spread to the brain, causing encephalitis that killed half of the wild-type pups within three weeks. As with the blood infection, female LRRK2 knockouts fared poorly. They accumulated more reovirus in the brain than did males, and only a quarter survived to three weeks. Males, on the other hand, survived as well as controls.

Unexpectedly, female G2019S knock-ins also fared worse than wild-types. Both male and female knock-ins mounted a robust immune response—three times as many leukocytes infiltrated the brain as in wild-type mice, and peak viral loads only reached a tenth as high. Even so, female G2019S mice succumbed readily to the infection, having three times the risk of dying as female controls, whereas male knock-ins survived as well as controls. Altogether, the data from this study suggest that female mice mount a more robust LRRK2-mediated immune response than males, which protects them from a peripheral infection, but backfires in the brain, causing increased neuronal damage and death, the authors noted.

In addition, G2019S knock-ins produced 50 percent more α-synuclein in their brains than did wild-types. Unlike the other analyses, males and females were similar in this regard. The findings hint at a connection to Parkinson’s disease, suggesting that a brain infection could kick off α-synuclein accumulation. Schlossmacher and others have proposed that α-synuclein acts as an antimicrobial agent (Oct 2016 news; May 2017 news; Jul 2017 news). Notably, researchers have found a gender difference in people who carry the G2019S variant, with women more likely to develop Parkinson’s than men (Cilia et al., 2014; Marder et al., 2015; San Luciano et al., 2017). In general, men are more likely to get the disease.

The findings could focus attention on the potential role of systemic inflammation in PD, given that a blood infection boosted reactive oxygen species in the brain, the authors said. “We believe LRRK2’s role in immunity will spur interest in the role of the peripheral immune system in shaping brain health. Maybe modulating the peripheral immune response will benefit PD patients,” Shutinoski and Hakimi wrote to Alzforum.—Madolyn Bowman Rogers

Comments

1. • Eli Kammerman
     
   • Posted: 07 Oct 2019

   Since LRRK2 plays a role in controlling the immune response of dendritic cells to Aspergillus, polymorphisms in this kinase could be responsible for a subpar immune response to fungi that permits CNS infection, leading to Parkinson's disease as the toxic effects of fungal-derived ochratoxin A and 1-octen-3-ol destroy dopaminergic neurons.

   A defective immune response against fungi could be especially damaging if the fungi establishes long-term residence in the appendix, thereby producing a steady output of toxins which gradually damage CNS function. Findings that appendectomies reduce the risk of PD incidence in rural residents supports this argument, as rural residents are generally exposed to fungi more frequently than urban residents.

   References:

   Wong AY, Oikonomou V, Paolicelli G, De Luca A, Pariano M, Fric J, Tay HS, Ricciardi-Castagnoli P, Zelante T. Leucine-Rich Repeat Kinase 2 Controls the Ca2+/Nuclear Factor of Activated T Cells/IL-2 Pathway during Aspergillus Non-Canonical Autophagy in Dendritic Cells. Front Immunol. 2018;9:210. Epub 2018 Feb 8 PubMed.

   Killinger BA, Madaj Z, Sikora JW, Rey N, Haas AJ, Vepa Y, Lindqvist D, Chen H, Thomas PM, Brundin P, Brundin L, Labrie V. The vermiform appendix impacts the risk of developing Parkinson's disease. Sci Transl Med. 2018 Oct 31;10(465) PubMed.

   View all comments by Eli Kammerman

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References

News Citations

1. Do Immune Responses Promote, or Prevent, Parkinson’s Disease? 18 Apr 2018
2. LRRK Watchers’ Eyes Turn to Inflammation, Autophagy, Kinase 22 Mar 2013
3. Could Bacterial Amyloid Trigger Parkinson’s Pathology? 14 Oct 2016
4. Olfactory System Model Explores Antimicrobial Role for α-Synuclein 12 May 2017
5. Put ’Em Up: Does α-Synuclein Help Fight Microbes in the Gut? 1 Jul 2017

Research Models Citations

1. LRRK2 G2019S KI Mouse

Paper Citations

1. Cilia R, Siri C, Rusconi D, Allegra R, Ghiglietti A, Sacilotto G, Zini M, Zecchinelli AL, Asselta R, Duga S, Paganoni AM, Pezzoli G, Seia M, Goldwurm S. LRRK2 mutations in Parkinson's disease: confirmation of a gender effect in the Italian population. Parkinsonism Relat Disord. 2014 Aug;20(8):911-4. Epub 2014 Apr 25 PubMed.
2. Marder K, Wang Y, Alcalay RN, Mejia-Santana H, Tang MX, Lee A, Raymond D, Mirelman A, Saunders-Pullman R, Clark L, Ozelius L, Orr-Urtreger A, Giladi N, Bressman S, LRRK2 Ashkenazi Jewish Consortium. Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology. 2015 Jul 7;85(1):89-95. Epub 2015 Jun 10 PubMed.
3. San Luciano M, Wang C, Ortega RA, Giladi N, Marder K, Bressman S, Saunders-Pullman R, Michael J Fox Foundation LRRK2 Consortium. Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease. Ann Clin Transl Neurol. 2017 Nov;4(11):801-810. Epub 2017 Oct 19 PubMed.

Further Reading

News

1. Do Microbes in the Gut Trigger Parkinson’s Disease? 2 Dec 2016
2. Do Immune Cells Promote the Spread of α-Synuclein Pathology? 10 May 2019