VCP, Enzyme in Protein Degradation, May Be Blood Biomarker of Early Stages of Parkinson’s, Study Suggests

Blood levels of valosin-containing protein (VCP) — an enzyme involved in protein degradation — may be used as a biomarker of preclinical and early clinical stages of Parkinson’s disease (PD), a study suggests.

Reduced levels of VCP in the blood were found in both animal models of the disease and untreated patients at preclinical and early clinical stages of Parkinson’s.

The study, “VCP expression decrease as a biomarker of preclinical and early clinical stages of Parkinson’s disease,” was published in the journal Scientific Reports.

Parkinson’s neurodegeneration begins many years before the emergence of its hallmark motor symptoms. It is thus crucial to identify biomarkers of presymptomatic, or preclinical, stages of the disease so that patients can benefit more from neuroprotective treatments, potentially preventing further damage.

The VCP enzyme, also known as p97 in mammals, has several cellular functions, including the maintenance of protein balance and quality. It is involved in the degradation of faulty proteins in several cellular compartments, including the mitochondria, known as the cells’ powerhouses.

Increasing evidence suggests that changes in VCP activity may contribute to the development of several neurodegenerative diseases.

Mutations in the VCP gene are responsible for the development of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, a condition that can affect the muscles, bones, and brain. VCP mutations also have been identified in people with other neurodegenerative disorders, such as Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis (ALS).

Moreover, patients with neurodegenerative diseases and VCP mutations have been reported to show signs of Parkinson’s-like symptoms, including rigidity, tremor, and slowness of movements.

Together, the potential association of impaired VCP function with abnormalities in faulty proteins break-down, neurodegenerative conditions, and Parkinson’s-like symptoms suggest that changes in the enzyme may play a role in Parkinson’s development.

However, no studies have analyzed VCP levels during the early stages of idiopathic (sporadic) Parkinson’s — which is not caused by any mutations and is the most common form of the disease.

To learn more, a team of Russian researchers now evaluated the levels of VCP in a mouse model and in patients at the earliest stages of Parkinson’s.

The team analyzed VCP levels at different time points in both the blood and brain of mice injected with MPTP — a neurotoxin commonly used to induce the death of dopamine-producing neurons and create Parkinson’s models — that mimic early symptomatic stages of PD.

VCP levels also were measured in blood samples of 38 untreated and 14 treated patients with newly diagnosed Parkinson’s — considered to be early clinical stages — and in nine individuals with “predicted” Parkinson’s, considered late preclinical stages.

People with “predicted” Parkinson’s were those with an estimated PD diagnosis based on the presence of known predictors of the disease and who had a confirmed diagnosis two years later.

The researchers also analyzed blood samples of 23 people with neurological disorders other than Parkinson’s and 44 age-matched healthy individuals.

Data showed that VCP levels were similarly reduced in both mice and untreated patients at preclinical and early clinical stages of Parkinson’s disease.

The most significant changes in VCP levels observed in these mice were in the striatum and substantia nigra, two brain regions involved in Parkinson’s. Notably, after a significant reduction in VCP levels in these regions, there was an increase of VCP levels during the late presymptomatic stages, which the researchers hypothesized may be associated with compensatory mechanisms.

Changes in the enzyme levels in the substantia nigra were accompanied by similar alterations in the blood, suggesting that VCP blood levels “can be considered as biomarkers of the neurodegeneration of PD,” the researchers said.

In addition, untreated patients and people with “predicted” Parkinson’s had significantly lower VCP levels — by nearly two-fold — than healthy people. No significant differences were found between treated patients, people with other neurological diseases, and healthy volunteers.

These findings highlighted that a reduction in VCP levels is associated specifically with the development of Parkinson’s, and occurs in late preclinical and early clinical stages of the disease. It also showed that treatment influences the enzyme levels in Parkinson’s patients.

“These data suggest that a decrease in the relative levels of [VCP] might serve as a biomarker for the development of [disease] at the early clinical and preclinical stages of human PD [Parkinson’s disease],” the researchers said.