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Specific Parkinson’s Gene Mutation Linked to Higher Risk of Leukemia, Colon Cancer, Study Finds

gene mutation cancer risk

People with Parkinson’s disease who have a specific mutation in the LRRK2 gene may be 10 times more likely to develop leukemia, and twice as likely to have colon cancer, researchers report.

The researchers say this particular patient population should be closely monitored and screened for the early detection of cancer.

These findings, “Cancer Outcomes Among Parkinson’s Disease Patients with Leucine Rich Repeat Kinase 2 Mutations, Idiopathic Parkinson’s Disease Patients, and Nonaffected Controls,” were published in Movement Disorders.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. They usually result in the malfunctioning of lysosomes — special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration.

Different studies indicate Parkinson’s patients with a specific mutation in the LRRK2 gene, known as G2019S, have an increased risk of developing certain cancers compared with people with Parkinson’s disease of unknown cause.

“However, it is unclear whether the increased risk among LRRK2-PD [Parkinson’s disease] patients would be observed when compared with unaffected controls who are noncarriers of the G2019S mutation,” the researchers said.

Investigators from the Albert Einstein College of Medicine and Mount Sinai Beth Israel Medical Center sought to compare the prevalence of cancer among Parkinson’s patients with the LRRK2 mutation, people with Parkinson’s of unknown cause (also called idiopathic Parkinson’s), and healthy individuals (controls). To do so, they used a standardized questionnaire across seven international LRRK2 and Parkinson’s-related research centers.

The gathered data was then combined with previously published information to examine the associations between the LRRK2 G2019S mutation and several types of cancer.

Researchers studied the cancer outcomes of 257 LRRK2 G2019S Parkinson’s patients, 712 people with idiopathic Parkinson’s, and 218 genetically unrelated controls, ages 35 or older. On average, the Parkinson’s patients were 68.2 years old, while the control sample was 4 years younger, with a mean age of 64 years. Around 77% of study subjects were Ashkenazi Jews, who more commonly carry genetic mutations linked to Parkinson’s, such as LRRK2.

Results showed there were no significant differences in the cancer rates of all three study groups. In fact, the rates were similar: 32.3% for LRRK2 G2019S Parkinson’s patients, 27.5% for idiopathic Parkinson’s, and 27.5% for controls.

Nevertheless, individuals with the LRRK2 G2019S mutation had a 4.6-fold increased risk of developing leukemia, and a 1.6-fold higher risk of developing skin cancer. Researchers note that only 5 of the 257 people with LRRK2 G2019S Parkinson’s developed leukemia, compared with no cases in the idiopathic Parkinson’s group. Further analysis also suggested higher risks for colon and kidney cancers in LRRK2 G2019S Parkinson’s, but statistical significance was not attained.

Scientists then combined this data with that of a previous study, which led to an overall study pool totaling 401 people with LRRK2 G2019S Parkinson’s and 1,946 individuals with the idiopathic form of the neurodegenerative disorder.

The pooled analysis revealed that individuals with LRRK2 G2019S were 9.84 times more likely to develop leukemia, and 2.34 times more likely to develop colon cancer, in comparison with idiopathic Parkinson’s patients.

These findings indicate the LRRK2 G2019 mutation might be associated with the development of several types of cancer.

“We might consider that if someone is a carrier of the LRRK2 G2019S mutation they should be closely monitored for Parkinson’s and for certain cancers,” Ilir Agalliu, MD, PhD, associate professor in the department of epidemiology and population health at Albert Einstein College of Medicine, and first author of the study, said in a press release.

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Inflammatory Molecules in Blood May Help Predict Parkinson’s Progression, Study Suggests

machine learning, cytokines

Inflammatory molecules called cytokines may be a peripheral biomarker of Parkinson’s progression, especially of its characteristic changes in motor abilities, according to new research using machine learning.

The study, “Parkinson’s progression prediction using machine learning and serum cytokines,” appeared in the journal npj Parkinson’s Disease.

Besides altered immune responses and distinct populations of immune cells, increased levels of cytokines — small proteins secreted by cells of the immune system — may link inflammation with Parkinson’s. This has been seen in asymptomatic carriers of the G2019S mutation in the LRRK2 gene, which accounts for 1–5% of all Parkinson’s cases. Still, the extent to which peripheral cytokines may trigger the disease remains unclear.

Increasing evidence suggests that Parkinson’s may start in the periphery (for example, in the gut), possibly enabling the identification of markers of disease progression that could improve outcomes for patients and lead to better trial design.

Researchers at The University of Sydney, Australia, used machine learning to further assess the correlation between peripheral inflammatory cytokines and Parkinson’s symptoms. They analyzed serum samples from 160 patients (mean age 68–69, ages 57–58 at diagnosis), 80 of whom (40 men) had the G2019S mutation and 80 who did not (54 men), all followed within the Michael J Fox Foundation Parkinson’s Progression Markers Initiative. They then used machine learning models to predict clinical outcomes at two years.

Comparing the two groups, patients who carried the G2019S mutation had milder motor disease and less severe hyposmia — a reduced sense of smell — as assessed with the Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III) and the University of Pennsylvania smell identification test. At baseline (study start), mutation carriers also had higher levels of the cytokines PDGF and MCP1 than those in the group of idiopathic (of unknown cause) Parkinson’s disease.

One year later, the scientists assessed blood serum samples from 126 of these patients. Results revealed that two cytokines, GCSF and interleukin (IL)-5, had the greatest variation. However, only the levels of one cytokine, IL-1RA, differed between the two groups.

Clinically, the patients showed more severe motor symptoms and depression, which were associated with a significantly decreased (worse) score in the Schwab and England activities of daily living (ADL) scale.

A subsequent analysis showed that, among a subset of 76 patients, higher baseline levels of 14 cytokines correlated with greater (worse) findings on the geriatric depression scale over two years. A similar link was found between seven cytokines and motor function. IL-5 and GCSF were among the cytokines whose levels correlated with both scales.

Using machine learning, researchers observed that two cytokines, MIP1 alpha and MCP1, made the biggest peripheral contribution to predicting motor symptom severity using the Hoehn and Yahr and UPDRS III scales, respectively.

As such, higher levels of these molecules were associated with faster motor deterioration.

In turn, the cytokines IL-6 and IL-4 were the primary contributors to predicting geriatric depression. All top cytokine contributors were also good predictors of the Schwab and England ADL scale scores.

Using cytokines improved predictions by 20% over clinical data alone. As for other analyzed variables, age and gender were among the top 10 contributors to predicting ADL and UPDRS-III scores, respectively.

“These results provide information on the longitudinal assessment of peripheral inflammatory cytokines in [Parkinson’s] and give evidence that peripheral cytokines may have utility for aiding prediction of [Parkinson’s] progression,” the scientists wrote.

Future studies should use a larger and more diverse group of patients, and assess the potential impact of medications on both clinical outcomes and cytokines levels, the researchers added.

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Abnormal Brain Cell Type Leads to Parkinson’s-Related Neurodegeneration, Study Contends

brainstem cells

Scientists have found that an abnormal version of brain cells called astrocytes contribute to the accumulation of alpha-synuclein protein, the main component of Parkinson’s disease hallmark Lewy bodies.

Their study, “Patient-specific iPSC-derived astrocytes contribute to non-cell autonomous neurodegeneration in Parkinson’s disease,” was published in Stem Cell Reports.

Parkinson’s disease is linked to degeneration of the ventral midbrain (relating to the inferior part of the brain), a region that houses dopamine-releasing neurons.

Post-mortem analysis of Parkinson’s disease brain tissue has revealed astrocytes accumulate toxic amounts of alpha-synuclein during the disease process. Research also suggests that this toxic protein can be taken up and spread from astrocytes to neurons, causing neuronal death.

Astrocytes are star-shaped cells that outnumber neurons by fivefold. Found in the central nervous system, astrocytes are known as housekeeping cells because they care for neurons, nurture them and “clean up” after them.

Investigators set up to further investigate a role for Parkinson’s disease-related astrocyte dysfunction in midbrain nerve cell death.

They generated astrocytes and ventral midbrain dopaminergic neurons from induced pluripotent stem cells (iPSCs) of healthy individuals and of patients with the LRRK2 G2019S mutation, the most commonly found mutation in Parkinson’s disease.

iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell needed.

Although LRRK2’s main function is not known, it seems to play a key role in mitochondria — cells’ powerhouses — namely in autophagy, a process that allows cells to break down and rebuild their damaged components.

Healthy neurons and Parkinson’s astrocytes were together in the same lab dish to study their cellular interactions. Results revealed a significant decrease in the number of healthy ventral midbrain dopaminergic neurons when cultured together with Parkinson’s disease astrocytes, which was associated with astrocyte-derived alpha-synuclein aggregation.

Healthy neuronal death was caused by the shortening and disintegration of the cells’ projecting branches, known as axons and dendrites.

When healthy astrocytes were cultured with Parkinson’s neurons, the housekeeping cells partially prevented the appearance of disease-related cellular changes and alpha-synuclein buildup in the diseased neurons.

“We found Parkinson’s disease astrocytes to have fragmented mitochondria, as well as several disrupted cellular degradation pathways, leading to the accumulation of alpha-synuclein,” the study’s co-first author Angelique di Domenico, PhD, said in a press release.

Because Parkinson’s astrocytes had high levels of alpha-synuclein in them, researchers hypothesized that the toxic protein could be transferred to healthy dopamine-producing neurons and cause the damage they had previously observed.

Using the CRISPR-Cas9 gene editing tool, the team generated two new astrocyte lines (representing one Parkinson’s patient and one healthy control). This allowed them to “tag” alpha-synuclein within living cells and track the protein as it was generated by astrocytes and transferred to dopamine-producing neurons.

As expected, alpha-synuclein in Parkinson’s astrocytes accumulated at abnormally high levels and, upon culture with healthy dopamine-producing neurons, a direct transfer of astrocytic alpha-synuclein to neurons was observed.

Researchers then used this gene-editing technology to generate Parkinson’s astrocytes that lacked the LRRK2 G2019S mutation. Abnormal alpha-synuclein accumulation did not occur in gene-corrected astrocytes and upon culture with healthy neurons, there was no accumulation of alpha-synuclein or decrease in neuron survival.

Researchers then treated Parkinson’s astrocytes with a chemical designed to correct the cells’ disrupted clean-up system.

“We were elated to see after treatment that the cellular degradation processes were restored and alpha-synuclein was completely cleared from the Parkinson’s disease astrocytes,” di Domenico said. “These results pave the way to new therapeutic strategies that block pathogenic interactions between neurons and glial cells.”

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