Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s


The protein RasGRP1 is a key culprit for involuntary movements that arise from dopamine replacement therapies used to treat Parkinson’s disease, a new study done in animals suggests.

Targeting this protein may be a therapeutic strategy to prevent these motor problems, while still receiving the benefits of treatment.

The study, “RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease,” was published in Science Advances.

Parkinson’s disease is caused by the death of nerve cells in the brain that make the neurotransmitter dopamine. Therapies designed to increase the amount of dopamine in the brain, including levodopa (l-DOPA) and its derivatives, are staples of Parkinson’s treatment.

Although the effectiveness of these treatments is well-established, long-term use is associated with the development of involuntary movements called dyskinesia. However, exactly which molecular mechanisms are responsible for this side effect is not clear.

Previous research implicated a protein called Rhes in the development of  dyskinesia. In the new study, researchers examined the role of a related protein, RasGRP1 (Ras-guanine nucleotide-releasing factor 1). This protein is known to activate Rhes, and it has been shown to be active in certain blood cells. But its role in the brain is less clear.

Researchers first used a mouse model of Parkinson’s in which dopamine-producing neurons are killed by means of a specific toxin (6-hydroxydopamine). The researchers modeled Parkinson’s both in wild-type mice and in mice that had been genetically engineered to lack RasGRP1.

Both types of mice displayed similar Parkinson’s-like symptoms, and l-DOPA treatment resulted in similar improvement in these symptoms in both types. However, mice lacking RasGRP1 displayed significantly fewer abnormal involuntary movements with long-term l-DOPA treatment.

Additionally, in wild-type mice, l-DOPA treatment induced significantly higher levels of RasGRP1 in the mice’s brains. This finding also was replicated in a macaque (a type of monkey) model of Parkinson’s disease.

“Since monkey model for PD [Parkinson’s disease] can mimic more signs and symptoms of human PD, our finding strengthens the translational relevance of RasGRP1 in PD treatment,” the researchers wrote.

Additional biochemical studies indicated that RasGRP1 is involved in dyskinesia through the activation of the proteins mTOR and ERK (as well as other associated proteins).

These proteins have been implicated previously in l-DOPA-induced dyskinesia (LID). However, they play many important roles in different types of cells throughout the body, so it’s difficult to therapeutically target them without significant side effects. In contrast, the lack of functional RasGRP1 in mice did not result in noteworthy physiological problems, apart from some mild deficits related to the development of cells in the thymus, an organ that’s part of the immune system.

Because of this, “… we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” study co-author Srinivasa Subramaniam, PhD, a professor at Scripps Research, said in a press release.

Since mice and humans are biologically distinct in many important respects, further research will be needed to determine the safety profile of treatments intended to block RasGRP1. Nonetheless, this study provides a theoretical foundation for the possible utility of such treatment strategies.

“There is an immediate need for new therapeutic targets to stop LID,” Subramaniam said. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”

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Activated Immune T-Cells Infiltrate the Brain and Promote Neurodegeneration in Primate Models of Parkinson’s

Activated Immune T-Cells

Activated immune T-cells can infiltrate the brain and promote neurodegeneration in non-human primate models of Parkinson’s during the chronic stages of the disease, a study has found.

Results of the study, “Chronic infiltration of T lymphocytes into the brain in a non-human primate model of Parkinson’s disease,” were published in the journal Neuroscience.

Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation.

Recent studies have suggested that activated T-cells, which are immune cells that are responsible for destroying other cells or microbes seen as a threat by the immune system, also can play a key role in Parkinson’s neurodegeneration.

Studies in non-human primate models of induced-Parkinson’s have reported the infiltration of these activated T-cells in the brain’s substantia nigra a month after treatment with MPTP during the acute phase of the disease. (MPTP is a neurotoxin that induces brain inflammation and often is used to trigger the onset of Parkinson’s in different animal models.)

“[H]owever, T lymphocyte infiltration into the brain during the chronic phase after MPTP injection in NHP [non-human primate] models remains unclear. We believe that a better understanding of this phenomenon will help identify the neuropathological mechanisms underlying PD [Parkinson’s disease] in humans,” the researchers wrote.

In mice models of the disease, the chemokine RANTES also has been associated with the infiltration of activated T-cells into the brain and with the development of Parkinson’s. (Chemokines are small molecules that mediate and regulate immune and inflammatory responses.)

A team of Korean researchers investigated the mechanisms underlying the infiltration of activated T-cells during the chronic stage of the disease in non-human primate models of induced-Parkinson’s.

In addition to evaluating the infiltration of T-cells in the brain 48 weeks after animals received an injection of MPTP, investigators also assessed changes in the levels of RANTES in the animals’ blood, and assessed microglia activation. (Microglia activation refers to the process by which microglia — nerve cells that support and protect neurons — become overactive, triggering brain inflammation.)

A total of five animals were injected with MPTP and three received a saline injection (controls).

Compared to saline-treated animals, those treated with MPTP showed signs of local chronic infiltration of activated T-cells in different regions of the brain’s striatum — a brain region responsible for controlling body movements — and substantia nigra.

Moreover, in animals treated with MPTP, this was accompanied by the loss of dopaminergic neurons, abnormal microglia morphology, and chronic normalization of the levels of RANTES in the blood 24–48 weeks post-injection, indicative of inflammation.

“This study confirms the involvement of [T-cell] infiltration in MPTP-induced NHP [non-human primates] models of PD. Further, these findings reinforce those of previous studies that identified the mechanisms involved in [T-cell]-induced neurodegeneration,” the researchers wrote.

“The findings of chronic infiltration of T lymphocytes in our NHP model of PD provide novel insights into PD pathogenesis and the development of preventive and therapeutic agents,” they stated.

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Iron Accumulation in Brain Detected With High-Resolution MRI Technique, Animal Study Shows

iron accumulation

An experimental model of Parkinson’s in non-human primates leads to the accumulation of iron — known to contribute to the underlying causes of the disease — in a brain area linked to motor control. This metal accumulation can be detected using a neuroimaging technique called susceptibility-weighted imaging, according to recent research.

The study, titled “The role of iron in Parkinson’s disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry,” was published in Life Sciences.

Higher-than-usual iron levels have been found in a brain region — called the substantia nigra — in Parkinson’s patients. This brain area, which plays a key role in motor control, is particularly affected during the course of the neurodegenerative disease.

In non-human primates, scientists have observed that this iron accumulation is accompanied by the loss of neurons that produce the neurotransmitter dopamine. That chemical messenger is in short supply in Parkinson’s. Such high levels of iron also are thought to be correlated with an increased severity in motor deficits.

Various imaging techniques have been used to study Parkinson’s disease in distinct animal models and have been found to produce consistent results. However, such methods are rarely validated.

Now, using cynomolgus monkeys, or crab-eating macaques, researchers investigated the role of metal accumulation in the striatum and midbrain (both motor control areas) in Parkinson’s. The researchers evaluated the use of susceptibility-weighted imaging (SWI) to measure iron deposits in the brains of Parkinson’s monkeys.

SWI is a high-resolution magnetic resonance imaging (MRI) technique that is sensitive to the magnetic properties of blood, iron, and calcifications, or calcium build-up in the body. These substances disturb magnetic fields, producing a not-so-clear image in a standard MRI scenario. SWI provides a unique contrast, generating 3D high-spatial-resolution images.

The animals received a left-side carotid artery injection of MPTP, a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. The carotid artery is one of the arteries that supplies the brain with blood.

An SWI-MRI was performed before and after the monkeys had received the MPTP injections.

Around 4-to-6 days after the injection, the monkeys exhibited limb muscle stiffness and limb postural tremor, and lost the ability to move their muscles freely (called akinesia). Importantly, these effects were only observed on the body side opposite, or contralateral, to the injection’s site.

The MRI results indicated there were higher-than-usual iron deposits in the MPTP-lesion side of the substantia nigra compared with the opposite side in the same animal. Similar results were found when these animals were compared with the control group of monkeys, which had been injected with a saline solution. Despite this indication, statistical significance was not attained.

Nevertheless, “MPTP did not affect the iron levels in other brain regions of monkeys,” the researchers said.

Post-mortem analysis of brain samples revealed that MPTP treatment provoked the loss of dopamine-producing neurons in the substantia nigra. The scientists reported that approximately 67.4% of dopaminergic nerve cells were lost in the substantia nigra on the injection side, while 30.0% were lost in the contralateral (opposite) side.

Neuronal loss in the substantia nigra on the injection’s side was correlated with worse behavioral performance and with motor impairment.

Biochemical analysis showed that MPTP increased iron levels in the injection’s side of the animals’ midbrain, but not in the striatum. However, calcium and manganese levels, which have been previously linked to Parkinson’s molecular mechanism, were unaffected by MPTP treatment.

“Taken together, the results confirm the involvement of [substantia nigra] iron accumulations in the MPTP-treated monkey models for [Parkinson’s disease], and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of [Parkinson’s disease],” the researchers concluded.

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