LRRK2 Gene Mutation Protects Against Infection But Increases Parkinson’s Risk Via Inflammation, Study Suggests

LRRK2, inflammation

Although it may be protective against infections, a specific mutation in the LRRK2 gene — the gene linked to most inheritable mutations that can cause Parkinson’s disease — may increase Parkinson’s risk by promoting inflammation in the brain, according to new research.

The study, “Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner,” appeared in the journal Science Translational Medicine.

Mutations in the LRRK2 gene are found in about 2% of people with Parkinson’s, with different studies reporting a greater frequency in women. But a mutated LRRK2 also has been associated with greater risk for two other disorders in which inflammation is a key component: Crohn’s disease (CD), which targets the gut, and leprosy, which affects the peripheral nervous system.

LRRK2 is highly expressed in several types of immune cells, including macrophages and natural killer cells. This suggests it plays a role in innate immunity — nonspecific defense mechanisms prompted by any given microbe.

To test this hypothesis, a team from Canada assessed LRRK2 expression in human white blood cells and tissues during inflammation, and studied viral and bacterial infections in Lrrk2 mutant animals.

First, the team found that neutrophils — immune cells that travel to the site of an infection — were the cell type with the highest expression of LRRK2 in healthy participants. Immune–related tissues, such as the bone marrow and lymph nodes, showed abundant RNA levels of LRRK2. RNA is the genetic template that gives origin to proteins.

Then, the investigators found significant protein production in gut samples of patients with Crohn’s disease, and in brain tissue of people infected by HIV, rabies virus, or virally infected peripheral nerve roots. All of these are characterized by inflammation.

Taking this data together with findings in Parkinson’s patients, which showed strong LRRK2 production in brain white blood cells, the team “concluded that LRRK2 appears to be abundant in infiltrating leukocytes of human tissues during acute or chronic inflammation.”

In mice, the researchers used a sepsis model — inoculation with Salmonella typhimurium — and an encephalitis model, induced by infection with reovirus, to assess the role of LRRK2 in acute bacterial and viral infection.

They found that, in both models, normal (wild-type) Lrrk2 expression was protective compared with complete Lrrk2 absence or production from only one gene copy. Female mice lacking Lrrk2 showed a stronger inflammatory response than male animals that lacked the gene, the researchers noted.

Then, the scientists studied the p.G2019S mutation — the most common mutation in LRRK2 — which increases the activity of the LRRK2 protein. Carrying this mutation enhanced inflammation and boosted the protective effect of normal Lrrk2, with reduced bacterial growth and longer survival during sepsis. This greater protection was mediated by the higher number of myeloid cells — monocytes, macrophages and neutrophils — in the spleen.

In mice with sepsis and with the Lrrk2 mutation, the scientists also observed increased oxidative damage in the spleen and the brain.

“When mice with the Parkinson’s-linked mutation were infected with Salmonella bacteria, we saw very high levels of  in the brain, almost twice as high as in normal mice,” Bojan Shutinoski, PhD, the study’s first author, said in a press release. “This was particularly surprising because the bacteria never even entered their nervous system!”

Mouse pups with encephalitis and no Lrrk2 had increased mortality — especially females — and increased activation of microglia, the resident immune cells of the brain. Animals with the p.G2019S mutation showed reduced survival despite lower viral levels. These mice also exhibited greater brain infiltration of white blood cells, and higher concentrations of the alpha-synuclein protein — the main component of Parkinson’s hallmark Lewy bodies.

The higher mortality in mice with the p.G2019S mutation was likely due to increased enzymatic activity of Lrrk2, as animals with a mutation (p.D1994S) that suppresses this activity showed greater survival.

“Our findings support a growing body of evidence that the LRRK2 protein functions in immune cells both within the brain … and the periphery,” the investigators said.

“Everyone thought that LRRK2’s primary role was in the brain, because of its association with Parkinson’s disease. But our research shows for the first time that its primary role is probably in the immune system,” said Michael Schlossmacher, MD, the study’s senior author and a neurologist at The Ottawa Hospital.

“Our research suggests that certain mutations in LRRK2 enhance inflammation and help the body to defend itself better against viruses and bacteria, but this enhanced inflammation could also increase the risk of Parkinson’s and other brain diseases,” added Schlossmacher, also a professor at the University of Ottawa Brain and Mind Research Institute.

The findings are in line with other additional studies suggesting that Parkinson’s may start outside the brain, and showing a link with Crohn’s disease.

“If this theory about LRRK2 is correct, it could open the door for the monitoring of infections as a key risk element for prediction, early detection and prevention of Parkinson’s, and importantly, for new treatment approaches in general,” Schlossmacher said.

The results also may have implications for the clinical development of therapies that block LRRK2 activity.

“Our research suggests that these drugs may well succeed in safely reducing excessive inflammation,” Shutinoski said. “However, we should be careful not to abolish LRRK2 function altogether, as this could make people more susceptible to infections, in particular when being treated potentially for years.”

The post LRRK2 Gene Mutation Protects Against Infection But Increases Parkinson’s Risk Via Inflammation, Study Suggests appeared first on Parkinson’s News Today.

Older IBD Patients Show Increased Risk for Parkinson’s Disease, Study Suggests

IBD risk factor

Older patients with inflammatory bowel disease (IBD) are more likely to develop Parkinson’s disease than those without the condition, a meta-analysis suggests.

Whether the same association exists for younger patients — ages 59 or younger — remains to be determined, according to the researchers.

The study, “Older patients with IBD might have higher risk of Parkinson’s disease,” was published in the journal Gut.

The chronic activation of pro-inflammatory mechanisms, which occurs in autoimmune conditions, has been increasingly recognized as a critical contributor of neurodegenerative disorders.

Studies suggest that this may happen due to the “gut-brain axis” — the two-way communication between the nervous system and the intestine that monitors gut function and links certain regions of the brain to intestinal functions, such as immune activation or intestinal permeability.

In line with the findings, some studies have already reported that patients with IBD — an autoimmune condition characterized by chronic inflammation of the gut — are 22-41% more likely to develop Parkinson’s than those without IBD.

However, a case-control study that examined Medicare data from 89,790 Parkinson’s cases and 118,095 population-based controls suggested that IBD actually reduced the risk for Parkinson’s by 15%.

To clarify this association, a team at Sichuan University in China reviewed all studies investigating the link between IBD and risk of Parkinson’s. Five studies met the inclusion criteria defined by the team, including a total of 9,174,766 participants.

Overall, IBD patients did not have a significantly higher risk of Parkinson’s than reference individuals, nor did patients with ulcerative colitis or Crohn’s disease — the two main forms of IBD — when examined individually.

However, patients 60 years or older were found to have a 32% higher risk of developing Parkinson’s. Patients 50 years or younger did not show this association, the researchers said.

“Our meta-analysis showed that patients with IBD did not have an increased risk of PD; however, subgroup analysis with cohort studies showed that they might be associated with increased risk of PD,” the researchers wrote.

“Age has been regarded as an important risk factor for Parkinson’s disease,” they added, but the findings suggest that “age at IBD diagnosis might be a risk factor of Parkinson’s disease.”

Interestingly, the team found that some studies reported medication-related side effects in the IBD population that resembled parkinsonism in the older population.

“It is necessary to take it into consideration whether older people will take more medications, and whether these medications lead to a higher risk of Parkinson’s also needs further studies to verify in the future,” they said.

Additional well-designed observational studies are still warranted to further explore the risk of Parkinson’s disease within the younger IBD population, the team noted.

The post Older IBD Patients Show Increased Risk for Parkinson’s Disease, Study Suggests appeared first on Parkinson’s News Today.

Inflammatory Bowel Disease Linked to Risk of Parkinson’s in Large Review Study

People with inflammatory bowel disease (IBD), an umbrella name for disorders marked by prolonged inflammation of the digestive tract, are at a higher-than-usual risk for Parkinson’s disease, a review study involving 8.9 million IBD patients suggests.
The study, “The risk of Parkinson’s disease in inflammatory bowel disease: A systematic review and meta-analysis,” was published in the journal Digestive and Liver Disease.
Inflammatory bowel disease (IBD) is a term that includes two main disorders — ulcerative colitis and Crohn’s disease — and is characterized by an imbalanced immune response that triggers prolonged inflammation of the digestive tract.
Inflammation in ulcerative colitis is confined to the colon (large intestine), while in Crohn’s disease it can involve any part of the digestive system. But inflammation in Crohn’s is most common at the end of the ileum (the last section of the small intestine) or the colon.
Several studies have reported that some of the inflammatory pathways impaired in Parkinson’s are also found in IBD. Certain population-based studies have also reported an increased prevalence of Parkinson’s among IBD patients, but the link between both disorders remains controversial. Another follow-up study failed to confirm those initial findings.
Researchers in China conducted a meta-analysis of published literature focusing on Parkinson’s risk in IBD using two databases, PubMed and Embase, and including in their search the keywords “ulcerative colitis” and “Crohn’s disease.” For the meta-analysis, they included cohort or case-control studies with patients diagnosed with IBD, either ulcerative colitis and Crohn’s disease, and whose main outcome was Parkinson’s.
Out of an initial pool of 172 studies, four studies accounting for a total of more than 8.9 million patients were included in the meta-analysis. (A meta-analysis is a statistical technique used to summarize in a quantitative manner the findings of multiple studies.)
Performed in the United States, Denmark, Sweden and Taiwan, these four studies assessed the incidence rate of Parkinson’s in IBD patients, specifically those with Crohn’s and ulcerative colitis. Three had been conducted in 2018, and one in 2016.
“To our knowledge, this is the first MA [meta-analysis] to focus on the risk of PD [Parkinson’s] in IBD patients,” the research team wrote. “Despite the small number of studies included, the patient numbers were large due to the population-based nature of the included studies.”
Pooled results of all studies suggested that an IBD diagnosis was associated with a 41% increased risk of developing Parkinson’s.
Assessing the risk of ulcerative colitis and Crohn’s disease separately, researchers found that both disease subtypes were linked to a higher Parkinson’s risk compared with age- and sex-matched controls — Crohn’s patients had a 28% higher risk of Parkinson’s, and those with ulcerative colitis a 30% increased risk, the study reported.
Among the IBD patients, the risk for Parkinson’s was not affected by gender, with similar rates seen in male and female patients, or by age.
Overall, this meta-analysis “identified an increased risk of PD in IBD patients,” the reseachers wrote, which “remained significant when separately analysing CD [Crohn’s disease] and UC [ulcerative colitis] subgroups.”
“More comprehensive and detailed MA using a larger number of studies are required to validate our

Source: Parkinson's News Today

Parkinson’s May Share a Genetic Link with Crohn’s Disease, Study Finds

genetic link between Parkinson's, Crohn's

Mutations in the LRRK2 gene, a major genetic factor contributing to Parkinson’s disease, may likely affect the risk for Crohn’s disease, an inflammatory bowel disease, researchers at Mount Sinai in New York discovered.

The results suggest a potential genetic link between Crohn’s disease and Parkinson’s and common disease mechanisms. The findings should help researchers identify which patients are at risk for Crohn’s and aid in the development of new therapies that target these LRRK2 mutations.

“The presence of shared LRRK2 mutations in patients with Crohn’s disease and Parkinson’s disease provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases,” Inga Peter, the study’s lead author, said in a press release.

The study, “Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease,” was published in the journal Science Translational Medicine.

“Crohn’s disease is a complex disorder with multiple genes and environmental factors involved, which disproportionally affects individuals of Ashkenazi Jewish ancestry,” said Peter, a professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York.

In an attempt to identify new therapeutic targets for this disease, researchers performed a genome-wide association analysis using data from 2,066 patients with Crohn’s and 3,633 healthy individuals, all from Ashkenazi Jewish descent.

The analysis revealed that members of this population carry two mutations in the LRRK2 gene with opposite effects – one has a protective effect while the other increases the risk for Crohn’s.

Because the LRRK2 gene has long been associated with Parkinson’s disease, researchers went on to assess a possible link between the two diseases. They used a much larger study group of 24,570 people with Crohn’s, Parkinson’s, or with no disease. Each individual group had both Jewish and non-Jewish individuals.

Once again, researchers found that patients with Crohn’s disease had a higher prevalence of the the risk mutation, while those without the disease more commonly had the protective mutation. Interestingly, these mutations had similar effects for Parkinson’s patients, and the effects were seen in both Jewish and non-Jewish patients.

“We now demonstrate that these specific nonsynonymous variants in LRRK2 genetically link [Crohn’s disease] to [Parkinson’s disease],” the team wrote.

Overall, “these results point toward potential shared genetic and epidemiological links between these two diseases and can help identify a sub-group of patients with [Crohn’s disease] who are at a higher risk for developing [Parkinson’s disease],” researchers concluded.

The post Parkinson’s May Share a Genetic Link with Crohn’s Disease, Study Finds appeared first on Parkinson’s News Today.

Source: Parkinson's News Today