The Genetic Link Between Parkinson’s Disease and the Gut

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There is growing evidence that the status of the intestinal environment heavily influences CNS function. This gut-brain axis may play an important role in the development of neurological diseases, with Parkinson’s disease (PD) being no exception. One of the most recent pieces of evidence is the finding that several variants in the leucine-rich repeat kinase 2 ( LRRK2 ) gene raise or lower risk, not only for PD, but also for Crohn’s disease, an inflammatory bowel disorder. This work, published this month in the journal, Science Translational Medicine, was led by researchers Inga Peter and Judy Cho at the Icahn School of Medicine at Mount Sinai, New York.

These findings further highlight what an important player the gut is in PD pathogenesis. Gastrointestinal dysfunction is prevalent amoung PD patients and occurs early, well before the onset of motor symptoms. A chronic low-grade intestinal inflammation can ultimately lead to neuroinflammation, and neurodegeneration in PD may arise from a cascade of events starting in the gut, according to Malu Tansey, a speaker at NeuroConX 2015. This gut inflammation can also influence synuclein pathology, which appears in both the enteric and central nervous system. Heiko Braak has proposed that synuclein pathology, a key pathological hallmark of PD, actually begins in the gut of PD patients and travels to the brain via the vagus nerve.

Lrrk2

The immune status of the gut is strongly influenced by the gut microbiome, which constitutes 100 trillion microorganisms, the vast majority of which are living in the gut microbiota. In PD patients, the intestinal microbiome is altered and associated in a functional way to clinical phenotype, according to Filip Scheperjans, who is scheduled to present his work at the upcoming NeuroConX 2018 microbiome meeting in July. In a mouse model of PD, PD-derived microbiota enhanced alpha-synuclein-mediated motor dysfunction. These changes in microbiota are believed to be an early event in the development of PD and, with further investigation, may serve as an early biomarker and possibly even a therapeutic target.

The Peter and Cho study identified two variants of the Lrrk2 gene associated with Crohn’s disease. One, ND2081D, was associated with an increased risk for Crohn’s, while N551K appeared to be protective, associating with a lower risk.  The Lrrk2 mutation, G2019S, is the major genetic cause of familial and sporadic PD and has been shown to have deleterious effects through increased kinase activity. Similar elevations in kinase activity have been associated with ND2081D and both variants are able to bump up phosphorylation by about 30 percent in cell-free experiments, suggesting a similar mechanism of action. Association studies show the Lrrk2 variant, ND2081D, increases the risk of both Crohn’s disease and PD, suggesting these two diseases may share risk factors. This is consistent with the increased risk of PD amoung those patients suffering with inflammatory bowel disease.

While the mechansim underlying this co-morbidity requires further exploration, it offers yet another link in the connection between the gut and brain. For more information and cutting edge research on the role of the gut microbiome in brain health and disease, please join us at NeuroConX 2018.

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