Alpha-Synuclein RNA Molecule May Help Tell Apart Parkinson’s, DLB

The levels of a specific RNA molecule that provides instructions to make the alpha-synuclein protein may help, at an early stage, to distinguish patients with Parkinson’s disease from those with dementia with Lewy bodies, a study has found.

Researchers said these results highlight the importance of exploring the potential utility of RNA molecules — also known as transcripts — as disease biomarkers.

Future studies are needed to determine the value of these transcripts in predicting the progression of these two neurodegenerative disorders, the researchers said.

Their findings were reported in the study, “Expression Levels of an Alpha-Synuclein Transcript in Blood May Distinguish between Early Dementia with Lewy Bodies and Parkinson’s Disease,” published in the International Journal of Molecular Sciences.

Dementia with Lewy bodies, known as DLB, and Parkinson’s disease are both characterized by the accumulation of aggregates, or clumps, made up of misfolded alpha-synuclein protein. These alpha-synuclein aggregates, also known as Lewy bodies, are toxic to nerve cells and progressively destroy them, causing neurodegeneration.

One of the main differences between DLB and Parkinson’s is the brain region where these Lewy bodies first appear. In the case of patients with Parkinson’s, alpha-synuclein protein clumps tend to appear first in the substantia nigra, a brain region responsible for controlling voluntary movements. Meanwhile, in those with DLB, Lewy bodies appear scattered throughout the entire brain.

The clinical course of both disorders also differs, particularly regarding the onset of dementia and cognitive impairments. While symptoms of dementia are usually one of the first manifestations of DLB, in Parkinson’s they appear at more advanced stages of the disease.

Despite these differences, DLB is still challenging to diagnose, partly due to the high degree of similarities it has with Alzheimer’s disease, another neurodegenerative disorder.

“Therefore, the identification of biomarkers for the differential diagnosis of DLB is of paramount importance,” the researchers wrote.

Now, investigators in Spain reported the findings of a study that aimed to explore the usefulness of five different alpha-synuclein transcripts as biomarkers to distinguish patients with DLB from those with Parkinson’s. The five RNA molecules are SNCAtv1, SNCAtv2, SNCAtv3, SNCA126, and SNCA112.

Although all of these transcripts provide instructions to make the alpha-synuclein protein, they each have different properties. Each has a different sequence that depends on the type of splicing to which it was subjected. Splicing is the process by which certain non-coding genetic sequences, called introns, are removed from the final RNA molecule that will then be used for protein production.

In the study, the investigators measured the levels of four of these transcripts — SNCAtv1, SNCAtv2, SNCAtv3, and SNCA126 — in blood samples taken from 72 patients with DLB and 59 with Parkinson’s. Samples also were taken from 54 individuals of approximately the same age who had no neurological disorders, to serve as controls.

The levels of all five transcripts also were measured in post-mortem brain samples received from 16 donors each with DLB and Parkinson’s, and 13 donors who had shown no signs of having a neurological disorder.

In blood and post-mortem brain samples, SNCAtv1 was the most abundant transcript, with its levels making up about 60% of the total alpha-synuclein transcript levels measured.

Separate analyses of post-mortem brain samples revealed that the levels of two transcripts, SNCAtv1 and SNCA112, were significantly higher in DLB patients compared with controls. The levels of SNCAtv2 were also found to be much higher in brain samples from donors with Parkinson’s compared with controls. No other significant differences in transcript levels were found between the groups.

In blood samples, the levels of all four alpha-synuclein transcripts were found to be much lower in DLB patients, compared with those with Parkinson’s and the healthy controls.

Additionally, there was a correlation between disease duration and the levels of alpha-synuclein transcripts: the shorter the duration from DLB onset, the lower the alpha-synuclein transcript expression levels in the blood.

Specifically, the levels of SNCAtv3 in the blood of DLB patients were lower at the early stages of the disease and tended to increase gradually as the disorder progressed. Conversely, in people with Parkinson’s, SNCAtv3 levels were higher at the earlier stages of the disease and tended to drop over time.

According to the researchers, this opposite trend in SNCAtv3 levels suggests “that its amount may be an early, DLB specific biomarker,” while its distinct evolution over the course of DLB and Parkinson’s may be “reflecting differences in brain alpha-synuclein aggregation rates associated with differences in disease courses.”

Although no correlation between alpha-synuclein transcript expression and disease onset was found in DLB, in Parkinson’s a “significant weak” but moderate positive correlation was found between age at disease onset and the levels of SNCAtv1, SNCAtv2, and SNCAtv3.

Namely, the expression of SNCAtv1 and SNCAtv2, but not of SNCAtv3, was significantly higher in people with Parkinson’s who showed their first symptoms before the age of 70, when compared with both Parkinson’s patients with an onset at 70 years or later, and controls.

“In conclusion, SNCA transcripts showed a disease-specific increase in the brain and were diminished in blood of LBD [Lewy body diseases] patients. SNCAtv3 expression was decreased in early DLB and increased in early PD [Parkinson’s disease] and could be a biomarker for early DLB diagnosis,” the researchers concluded.