Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023;13(3):279-296.
doi: 10.3233/JPD-230021.

Immunological Features of LRRK2 Function and Its Role in the Gut-Brain Axis Governing Parkinson's Disease

Inga Peter  1 , Warren Strober  2
Affiliations
Review

Immunological Features of LRRK2 Function and Its Role in the Gut-Brain Axis Governing Parkinson's Disease

Inga Peter et al. J Parkinsons Dis. 2023.

Abstract

Emerging evidence implicates intestinal involvement in the onset and/or progression on the selective degeneration of dopaminergic neurons characterizing Parkinson's disease (PD). On the one hand, there are studies supporting the Braak hypothesis that holds that pathologic α-synuclein, a hallmark of PD, is secreted by enteric nerves into intestinal tissue and finds its way to the central nervous system (CNS) via retrograde movement in the vagus nerve. On the other hand, there is data showing that cells bearing leucine-rich repeat kinase 2 (LRRK2), a signaling molecule with genetic variants associated with both PD and with inflammatory bowel disease, can be activated in intestinal tissue and contribute locally to intestinal inflammation, or peripherally to PD pathogenesis via cell trafficking to the CNS. Importantly, these gut-centered factors affecting PD development are not necessarily independent of one another: they may interact and enhance their respective pathologic functions. In this review, we discuss this possibility by analysis of studies conducted in recent years focusing on the ability of LRRK2 to shape immunologic responses and the role of α-synuclein in influencing this ability.

Keywords: α-synuclein; Gut-brain axis; LRRK2; Parkinson’s disease; enteric nervous system; intestinal inflammation.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
Schematic representation of LRRK2 domain structure. Respective locations of the amino acid substitutions previously linked to Parkinson’s disease and inflammatory bowel disease are shown. ARM, armadillo; ANK, ankyrin repeat region; LRR, leucine-rich repeat; ROC, Ras of complex proteins; COR, C terminal of ROC; KIN, mitogen-activated protein kinase; WD40, WD40 protein-protein interaction domain.
Fig. 2
Fig. 2
The gut-brain axis in Parkinson’s disease (PD). In this concept of PD pathogenesis, macrophages in the gut lamina propria are induced by secreted pro-inflammatory cytokines in individuals carrying gain-of-function LRRK2 variants that express increased levels of activated LRRK2; stimulation of cells by α-synuclein from enteric nerves may also occur at this site but this is still unproven. Macrophages thus stimulated that gain entry into the circulation are attracted into brain tissue by chemokine-secreting microglia and in the brain tissue are induced to produce pathogenic inflammatory cytokines by as yet undefined stimuli, possibly including α-synuclein once again; these cytokines cause or aggravate neural degeneration. Also depicted are small intestinal Paneth cells whose function is regulated in part by LRRK2; thus, LRRK2 variants that affect this function and adversely regulate the composition of the gut microbiome may lead to PD by promoting gut inflammation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24, 197–211. - PubMed
    1. Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110, 517–536. - PubMed
    1. Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: A dual-hit hypothesis. Neuropathol Appl Neurobiol 33, 599–614. - PMC - PubMed
    1. de Guilhem de Lataillade A, Caillaud M, Oullier T, Naveilhan P, Pellegrini C, Tolosa E, Neunlist M, Rolli-Derkinderen M, Gelpi E, Derkinderen P (2023) LRRK2 expression in normal and pathologic human gut and in rodent enteric neural cell lines. J Neurochem 164, 193–209. - PubMed
    1. Xu E, Boddu R, Abdelmotilib HA, Sokratian A, Kelly K, Liu Z, Bryant N, Chandra S, Carlisle SM, Lefkowitz EJ, Harms AS, Benveniste EN, Yacoubian TA, Volpicelli-Daley LA, Standaert DG, West AB (2022) Pathological alpha-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain. Mol Neurodegener 17, 7. - PMC - PubMed

Publication types

MeSH terms

Substances