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Alpha-synuclein in Blood Serum May Be Early Parkinson’s Biomarker, Study Suggests

biomarker, alpha-synuclein

Measuring the amount of alpha-synuclein in tiny vesicles collected from blood serum may help diagnose early Parkinson’s and identify patients with different types of this disease.

The study with that finding, “Central Nervous System-Derived Exosomal Alpha-Synuclein in Serum May Be a Biomarker in Parkinson’s Disease,” was published recently in the journal Neuroscience.

As both resting and posture tremor may occur in the early stages of Parkinson’s, patients may be misdiagnosed with essential tremor. Similar to Parkinson’s, essential tremor is a progressive movement disorder, and it predominantly affects hands and arms.

Alpha-synuclein is the main component of Lewy bodies, characteristic protein aggregates that accumulate in brain cells of Parkinson’s patients.

Compared to unaffected individuals, Parkinson’s patients typically have lower levels of alpha-synuclein in their cerebrospinal fluid — the liquid surrounding the brain and spinal cord — which correlates with prognosis. However, measuring alpha-synuclein in the clinic has been precluded by the invasive nature of spinal tap and by the inconsistent results of plasma or serum samples.

Exosomes are tiny vesicles released by neurons and other cells, and have been implicated in the transmission of misfolded proteins, including alpha-synuclein in people with Parkinson’s. As such, researchers hypothesized that exosomes derived from the central nervous system (CNS) could be a peripheral biomarker of Parkinson’s disease.

The scientists recruited 38 newly diagnosed, untreated patients with early Parkinson’s divided into tremor-dominant (TD, 22 patients, mean age 62.7 years) and non-tremor-dominant (NTD, 16 patients, 62.1 years), who were compared to 21 patients with essential tremor (62 years) and 18 healthy controls.

Among the patients with Parkinson’s, those with TD had a shorter disease duration than the people with the NTD subtype (19.2 vs. 35.8 months). The age at disease onset did not differ in these two groups – 61.1 years in TD and 59.1 years in NTS patients.

The results revealed that Parkinson’s patients had lower levels of alpha-synuclein in CNS-derived serum exosomes than those with essential tremor or controls. Importantly, within Parkinson’s patients, those with the NTD type — which has been associated with more frequent depression, lack of motivation and impairment in activities of daily life — had lower amounts than those in the TD subset.

A subsequent analysis found that exosomal alpha-synuclein had a moderate potential to diagnose Parkinson’s disease and a great potential to diagnose non-tremor-dominant patients.

Of note, the amount of CNS-derived alpha-synuclein in exosomes was not significantly associated with disease duration or severity.

Overall, “CNS-derived exosomal [alpha]-synuclein in the serum may be regarded as a biomarker to identify [early Parkinson’s],” the scientists wrote.

Cautioning that studies with larger groups of patients and those with longitudinal monitoring are needed, the team further commented that assessing alpha-synuclein in serum exosomes also may help identify different Parkinson’s types.

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Manganese Exposure May Be Linked to Parkinson’s Development, Study Suggests

manganese

Exposure to the metal manganese may lead to the development of Parkinson’s disease by promoting the release from nerve cells of alpha-synuclein, the subsequent aggregation of which causes inflammation and neurodegeneration, according to a study.

The study, “Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein,” was published in the journal Science Signaling.

Increasing studies have reported that aggregated alpha-synuclein — the main component of Lewy bodies, a Parkinson’s characteristic — is able to migrate within the central nervous system (brain and spinal cord), a process associated with Parkinson’s progression.

Alpha-synuclein induces brain inflammation and neurodegeneration after being secreted from nerve cells in exosomes — tiny vesicles thought to play a role in cell-to-cell transmission of misfolded proteins.

Small amounts of manganese are essential for the proper functioning of certain enzymes in the body. However, exposure to this metal — which has a range of industrial uses as an alloy — in contaminated air and drinking water, as well as in agricultural products, may lead to a movement disorder called manganism with manifestations similar to those of Parkinson’s. Additionally, occupational exposure to manganese in welding fumes has been linked to a higher risk of parkinsonism, a general term for disorders causing movement problems that resemble Parkinson’s.

However, the precise mechanisms through which manganese exerts a neurotoxic effect, as well as its role in alpha-synuclein propagation, are not well-understood by scientists yet.

Researchers at Iowa State University conducted a range of in vitro (in the lab) and in vivo (in animal models) experiments to address this lack of knowledge as well as to evaluate whether exosomes are involved in the transmission of alpha-synuclein.

The in vitro assessments in dopamine-producing nerve cells of mice revealed that exposure to manganese induced the release of misfolded alpha-synuclein through exosomes. These exosomes were then taken up by immune cells called microglia, producing neuroinflammatory responses as reflected by the release of proinflammatory molecules TNF-alpha, interleukin (IL)-12, IL-1beta, and IL-6.

“These results support recent observations indicating that neuroinflammation plays a major role in [Parkinson’s],” the researchers wrote.

In a model of human dopaminergic neurons, exosomes caused toxicity or apoptosis — which refers to “programmed” cell death, as opposed to cell death caused by injury.

A subsequent imaging analysis found that orally delivered manganese accelerated cell-to-cell transmission of aggregated alpha-synuclein, leading to toxicity in dopamine-producing cells. This was assessed in mice injected with a viral vector to produce alpha-synuclein coupled with a fluorescent tag to enable visualization.

Mice that were given both the viral vectors and manganese exhibited more impaired motor function than those injected with the vectors alone, as well as severe loss of dopamine-producing nerve cells in the substantia nigra — an area of the brain known to be affected in Parkinson’s disease.

Researchers also found higher levels of alpha-synuclein in exosomes in blood samples from eight welders, at a mean age of 46 years, with no symptoms of Parkinson’s, compared with 10 healthy individuals used as controls.

“As a group, welders are at risk of prolonged exposures to environmental levels of metals, including [manganese],” the researchers wrote.

The team also observed that injecting alpha-synuclein-containing exosomes collected from cells exposed to manganese into the mouse striatum — a brain region connected to the substantia nigra that also shows lower levels of dopamine in Parkinson’s disease — induced more lethargic behavior as observed by reduced exploratory activity after six months. This was associated with an inflammatory response in the brain.

“Together, these results indicate that [manganese] exposure promotes [alpha-synuclein] secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models,” the researchers wrote.

“As the disease advances, it’s harder to slow it down with treatments,” Anumantha Kanthasamy, PhD, the study’s senior author, said in a press release. “Earlier detection, perhaps by testing for misfolded alpha-synuclein, can lead to better outcomes for patients. Such a test might also indicate whether someone is at risk before the onset of the disease.”

Kanthasamy is the Clarence Hartley Covault distinguished professor in veterinary medicine and the Eugene and Linda Lloyd endowed chair of neurotoxicology at Iowa.

The post Manganese Exposure May Be Linked to Parkinson’s Development, Study Suggests appeared first on Parkinson’s News Today.

Certain MicroRNAs Could Help Diagnose Parkinson’s, Study Suggests

microRNAs in Parkinson's

Specific microRNAs that are contained in tiny, cell-derived vesicles called exosomes may be biomarkers of Parkinson’s disease, according to a study.

The study, “Circulating exosomal miRNAs as diagnostic biomarkers in Parkinson’s disease,” was published in the journal European Review for Medical and Pharmacological Sciences.

MicroRNAs (miRNAs) are tiny bits of RNA that bind to messenger RNA (mRNA) — a molecule generated from DNA that contains the information to make proteins — to regulate gene expression, which is the process by which information in a gene is synthesized to create a working product, like a protein.

Abnormal plasma levels of miRNAs have been found in Parkinson’s patients. For example, while miR-505 — also implicated in cancer and hypertension — was reduced, miR-331-5p — also involved in cancer and chemotherapy resistance — was elevated in these patients.

In the cerebrospinal fluid, which fills the brain and spinal cord, miRNAs contained in exosomes may have diagnostic value for Parkinson’s patients. However, little is known about exosomal miRNAs from blood plasma, which have been suggested as a useful approach to diagnose Alzheimer’s.

Aiming to address this, researchers at Cangzhou Central Hospital in China collected blood from 52 Parkinson’s patients and 48 healthy participants used as controls. Parkinson’s patients included 28 men, at a mean age of 65.6 years with a mean disease duration of 5.3 years. Healthy individuals included 26 men, at a mean age of 61.2 years.

All patients had taken Parkinson’s medications for at least two weeks and had Mini-Mental State Examination cognitive scores within the normal range.

Among the used Parkinson’s medications, a levodopa/carbidopa combination was taken by all patients. Comtan (entacapone) was also common, taken by 20 patients (38.5%), while Zelapar (selegiline) was taken by 10 (19.2%), and Requip (ropinirole) taken by nine (17.3%).

Exosomes were isolated from blood samples, which were then analyzed for their levels of protein and miRNAs.

The exosomes were round or oval-shaped and contained the exosomal protein markers CD9, CD63, and Tsg101, confirming the presence of these tiny vesicles in plasma.

Among nine different miRNAs, the level of exosomal miR-331-5p was significantly higher and that of miR-505 was significantly lower in Parkinson’s patients than in healthy controls. In patients, miR-331-5p was mainly packaged in exosomes, which, according to the researchers, may mean it is later transferred to Parkinson’s-related cells to influence disease development.

In turn, miR-505 was essentially found in the plasma, indicating it may not be transferred to Parkinson’s by exosomes, but rather by other cells. However, this theory needs to be further studied, the team said.

These results provide “solid evidence that exosomal miR-331-5p and miR-505 could be biomarkers for [Parkinson’s],” the researchers wrote, and that “exosomal miR-331-5p and miR-505 have diagnostic values for [Parkinson’s].”

The post Certain MicroRNAs Could Help Diagnose Parkinson’s, Study Suggests appeared first on Parkinson’s News Today.

Source: Parkinson's News Today