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Mutation in ATP13A2 Gene Linked to Nerve Cell Health and Possibly Parkinson’s, Study Says

disease-causing mutation

A mutation in the ATP13A2 gene disrupts the transport of polyamines — positively charged molecules that interact with DNA and proteins to control cell growth, survival, and proliferation — killing nerve cells and potentially leading to Parkinson’s disease, a study reports.

The study, “ATP13A2 deficiency disrupts lysosomal polyamine export,” was published in the journal Nature.

The entry, exit, production, and breakdown of polyamines are all strictly controlled to ensure cell survival. When their levels inside cells rises too high, they start to be toxic, damaging and ultimately killing cells.

“Polyamines are essential molecules that support many cell functions and protect cells in stress conditions. But how polyamines are taken up and transported in human cells was still a mystery. Our study reveals that ATP13A2 plays a vital role in that process,” Peter Vangheluwe, PhD, an associate professor at KU Leuven and a senior study author, said in a press release.

ATP13A2, also known as PARK9, is a gene that provides instructions to make a protein responsible for the transport of polyamines within cells, and for regulating the activity of lysosomes — small cell compartments that digest and recycle different types of molecules.

ATP13A2 is thought to protect against genetic and environmental risk factors for Parkinson’s, and its lack of activity has been associated with several neurodegenerative disorders, including Kufor-Rakeb syndrome and early onset Parkinson’s disease, and lysosomal defects.

Despite knowing that ATP13A2 played a central role in Parkinson’s, scientists did not know how a mutation in this gene could lead to the onset of this disease.

A team of researchers at KU Leuven in Belgium and their colleagues found that defects in ATP13A2 compromise the transport of polyamines in lysosomes found inside nerve cells. Such compromised transport leads to cell death, and possibly to the onset of Parkinson’s.

In their experiments, investigators studied the function of the ATP13A2 transporter in mice neurons and human neuroblastoma cells (SH-SY5Y cells) cultured in a lab dish, as well as in roundworms that had been genetically engineered to produce mutated forms of ATP13A2.

When they inactivated Atp13a2 (the mouse equivalent of the human ATP13A2 gene) in mice neurons, cells became more susceptible to cell death triggered by polyamines, compared to normal nerve cells.

Exposure to polyamines also stunted the growth of healthy roundworms, having an even stronger effect in animals producing mutated forms of the transporter.

When they examined the function of ATP13A2 in more detail, they found the transporter sits on the surface of lysosomes and is responsible for carrying polyamines from lysosomes into the cytosol, the liquid-like substance that fills the interior of cells.

“Our experiments showed that polyamines enter the cell via lysosomes, and that ATP13A2 transfers polyamines from the lysosome to the cell interior. This transport process is essential for lysosomes to function properly as the ‘waste disposal system’ of the cell, where obsolete cell material is broken down and recycled,” Vangheluwe said.

Mutations in the ATP13A2 gene can compromise the activity of the protein and transport of polyamines, leading to a buildup of polyamines inside lysosomes and to a shortage of polyamines in the cytosol.

Lower levels of polyamines in the cytosol may increase cells’ vulnerability to toxic substances (e.g., reactive oxygen species and heavy metals) that are normally scavenged by these molecules, while the buildup of polyamines inside lysosomes may lead to their destruction, and ultimately to cell death.

“Mutations in the ATP13A2 gene disrupt this [lysosome] transport process, so that polyamines build up in lysosomes. As a result, the lysosomes swell and eventually burst, causing the cells to die. When this happens in the part of the brain that controls body movement, this process may trigger the motion problems and tremors related to Parkinson’s disease,” Vangheluwe said.

Investigators said more research is needed to understand how genetic mutations in ATP13A2 may be linked to other problems in Parkinson’s, including mitochondrial dysfunction and the accumulation of plaques in the brain. (Mitochondria are the cell compartments responsible for the production of energy; plaques result from the gradual buildup of certain proteins.)

Another important step, the researchers said, will be moving these findings to the clinic, in hope of discovering new ways to ease the symptoms of patients carrying mutations in ATP13A2.

“Now that we have unravelled the role of ATP13A2, we can start searching for molecules that influence its function. Our lab is already collaborating with the Centre for Drug Design and Discovery — a tech transfer platform established by KU Leuven and the European Investment Fund — and receives support from the Michael J. Fox Foundation,” Vangheluwe said.

The team believes this work may also help shed light on other age-related conditions, including cancer, heart disease, and other neurological disorders.

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LRRK2 Inhibitors May Benefit Parkinson’s Patients With and Without Genetic Mutation, Study Finds

LRRK2

Inhibiting the activity of LRRK2 kinase — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — may benefit patients both with and without this disease-related mutation, a study finds.

Molecules that block the activity of the LRRK2 kinase — such as DNL201 and DNL151, both being developed by Denali Therapeutics — are currently being tested in clinical trials.

The results of this study, “LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease,” were published in Neurobiology of Disease. The research was supported by the Michael J. Fox Foundation.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. Evidence indicates that in people with idiopathic Parkinson’s, in which the disease has no known cause, the LRRK2 protein is overly active, regardless of the patient’s mutation status — whether or not they have a mutated LRRK2. That overly active protein leads to the malfunctioning of lysosomes, the special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of  protein aggregates, or clumps, called Lewy bodies, which contribute to Parkinson’s and, therefore, neurodegeneration.

Therapies that can inhibit, or block LRRK2 are currently being tested in human clinical trials. However, it is still unclear whether blocking LRRK2 protein activity in people with idiopathic Parkinson’s can prevent lysosomal dysfunction and consequent neurodegenerative processes.

To learn more, investigators at the University of Pittsburgh now studied post-mortem brain samples, specifically from a motor brain region called the substantia nigra, which is severely damaged in Parkinson’s. The researchers characterized lysosomal abnormalities in the surviving dopaminergic neurons — the main source of dopamine, the loss of which is a hallmark of this disease — of idiopathic Parkinson’s patients.

When compared with healthy controls, Parkinson’s patients had more abnormal lysosomes. These changes occurred during the early stages of lysosomal development, the researchers found.

The team then investigated whether these post-mortem cellular findings could be replicated in an animal model of Parkinson’s. Rats were given two distinct dose regimens of rotenone, a pesticide that inhibits mitochondria, or the “powerhouses” of cells. Blocking mitochondria leads to cellular death and the onset of parkinsonian features.

Nine to 14 daily doses of rotenone reproduced many idiopathic Parkinson’s features, including lysosomal defects. This caused neurodegeneration in the striatum and substantia nigra, two brain areas involved in motor control.

Interestingly, five daily doses of the pesticide weren’t enough to cause cell death, but did increase the accumulation of Parkinson’s-related alpha-synuclein protein and produce changes in lysosomes.

“These data demonstrate that, in rotenone-treated rats, [alpha]-synuclein protein levels rise in the dopaminergic neurons prior to the onset of frank neurodegeneration,” the researchers said.

When overactive LRRK2 was blocked in rotenone-treated rats, the protein’s activity was reduced. That, in turn, improved the overall health of lysosomes and prevented the accumulation of alpha-synuclein. These effects were observed in animals without a genetic predisposition to develop Parkinson’s, suggesting that the LRRK2 kinase inhibitors may be effective beyond LRRK2-mutated patients.

“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” J. Timothy Greenamyre, MD, PhD, the study’s lead author, said in a press release.

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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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Brain Serotonin Changes May Be Early Warning Sign of Parkinson’s, Study Suggests

serotonin early warning

Changes to the serotonin system in the brain occur years before the development of motor symptoms in Parkinson’s — and may be an important early warning signal for the disease, a study suggests.

“Therefore, brain imaging of the serotonin system could become a valuable tool to detect individuals at risk for Parkinson’s disease, monitor their progression and help with the development of new treatments,” Heather Wilson, research associate at King’s College London and the study’s first author, said in a press release.

The study, “Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study,” was published in The Lancet Neurology.

Parkinson’s is characterized by the progressive death of brain cells that are responsible for producing dopamine, which eventually leads to the development of motor symptoms associated with the disease, including involuntary tremors or muscle contraction.

Studies have suggested that, in addition to changes in the dopaminergic system, Parkinson’s progression and symptoms may be associated with impaired signals from another important neurotransmitter, called serotonin. Serotonin transmits messages between nerve cells, and is thought to be active in constricting smooth muscles.

To further explore the role of serotonin in Parkinson’s progression, a team led by researchers from King’s College evaluated non-symptomatic carriers of an alpha-synuclein (SNCA) gene variant. That variant is an extremely rare mutation, but a well-known cause for hereditary Parkinson’s disease.

Individuals with mutations in the alpha-synuclein gene are almost certain to develop Parkinson’s during their lifetime, which makes them invaluable candidates to study the biological events that result in the development of the disease.

The study recruited 14 individuals who were carriers of the A53T variant in the SNCA gene, as well as 25 patients with idiopathic (of unknown cause) Parkinson’s disease, and 25 healthy matched volunteers who had no history of neurological or psychiatric disorders.

All participants were evaluated by positron emission tomography (PET) scans. PET scans use a specific dye that binds to the serotonin transporter, and evaluates serotonin metabolism in the brain. Participants also underwent several clinical assessments to determine motor and non-motor symptoms. They were evaluated for cognitive status, dopamine metabolism, and brain structural changes.

Among individuals who were SNCA mutation carriers, 50% were still asymptomatic —  at the premotor stage of the disease — and had dopaminergic deficits.

Compared with healthy controls, the premotor SNCA carriers showed reduced serotonin signals in several brain areas. SNCA carriers who still had normal dopamine transporters already showed “an average of 34% loss of serotonin transporters in raphe nuclei and 22% loss in the striatum compared with healthy controls,” the researchers said.

As the name indicates, a serotonin transporter is a protein that binds to and transports serotonin to different areas of the brain. Raphe nuclei are a type of brain receptor that decrease the release of serotonin. The striatum is a critical brain region involved in voluntary movement.

“Parkinson’s disease has traditionally been thought of as occurring due to damage in the dopamine system, but we show that changes to the serotonin system come first, occurring many years before patients begin to show symptoms,” said Marios Politis, MD, PhD, professor at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and senior author of the study.

Those who were SNCA carriers but had already been diagnosed with Parkinson’s disease showed more extensive deficits in the serotonin system, affecting even more areas of the brain. There was 48% serotonin transporter loss in the raphe nuclei, and 57%  loss in the striatum areas.

Further analysis revealed that low serotonin signals in the brainstem were associated with increased total scores on the Movement Disorder Score-Unified Parkinson’s Disease Rating Scale (MDS-UPSRS) — indicating higher disease burden. This occurred in all SNCA carriers, and in those with idiopathic Parkinson’s.

“Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualize premotor pathology of Parkinson’s disease in vivo [in the body],” the researchers said.

Future studies should focus on implementing serotonin transporter imaging as “an adjunctive tool for screening and monitoring progression” for those at risk for, or who already have Parkinson’s.

“This is one of the first studies to suggest that changes in serotonin signaling may be an early consequence of Parkinson’s,” said Beckie Port, PhD, research manager at Parkinson’s UK. “Picking up on the condition earlier and being able to monitor its progression would aid the discovery of new and better treatments that could slow the loss of brain cells in Parkinson’s.”

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