A biological clock based on DNA methylation, back-spliced exons, expression of LRRK2 mutations, and work on identifying new CSF proteins as markers of the disease – all were points of interest at the Michael J Fox Foundation’s New York meeting.
Circular RNAs, generated by back-splicing of exons, may arise as a result of cellular stress. They are highly enriched in the brain, accumulate in synapses, and it is possible that they pass between cells. Their half life of days or weeks and potential association with neurodegenerative diseases attracted the interest of Hermona Soreq (Jerusalem, Israel) and colleagues.
Preliminary data suggest subsets of circular RNAs are up- or down-regulated in the substantia nigra, amygdala and cortical regions from people with Parkinson’s disease (PD). Levels of circular RNAs in the substantia nigra correlate with age. Work is being extended to look at circular RNAs in blood.
Are circular RNAs associated with neurodegeneration?
Given the association between leucine-rich repeat kinase 2 (LRRK2) mutations and late-onset Parkinson’s disease, might a potential biomarker be found in levels of LRRK2 expression and phosphorylation in exosomes (vesicles arising in cells) from human biofluids such as urine? This question is being asked by Jean-Marc Taymans and colleagues at INSERM (Lille, France). Early work found no significant differences between people with PD and those without it; but studies continue.
CSF proteins. In the search for markers that might aid early diagnosis or chart disease progression or drug response, Fiona McAllister and colleagues (Caprion Biosciences, Montreal, Canada) used multiple reaction monitoring mass spectrometry to screen 185 proteins in CSF of people with PD and healthy controls. Reliable detection was possible in the case of 154 proteins, 39 of which were differentially expressed.
Of the 28 that were downregulated in PD, four were proteins involved in dopamine release and four in response to insulin. The eleven upregulated proteins were all related to processes involved in neuroinflammation.
Marking time with a biological clock
DNA methylation age (DNAm age) in the Parkinson's Progression Markers Initiative (PPMI) DNA methylation is involved in gene transcription and acts as mediator between genes and the environment. Can aspects of biological aging relevant to neurodegenerative diseases be captured by measuring the extent of methylation in specific tissues?
Building on Steve Horvath’s original concept of an epigenetic clock, the DNA methylation-based algorithm (DNAm age) was developed. On the look-out for markers that might identify people in the prolonged pre-motor phase of PD, Dena Hernandez and colleagues from the National Institute on Aging (Bethesda and Baltimore, USA) have calculated the DNAm age at 353 clock CpG sites in samples from five hundred participants in the PPMI.
Initial findings suggest biological age correlates strongly with chronological age. But, in an analysis of cross-sectional data, accelerated epigenetic aging is not associated with presence of PD. We need a longitudinal study to see if accelerated.
