Abstract
Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS. Our data indicate that reduced ccf-mtDNA is a component of PMS, concluding that it may indeed be a hallmark of broader neurodegeneration.
Highlights
Progressive multiple sclerosis (PMS) is a chronic, inflammatory, demyelinating disorder with progressive neurodegeneration (Stadelmann, 2011)
Similar to our previous work (Pyle et al, 2015a), and the work of others (Podlesniy et al, 2013; Varhaug et al, 2017; Leurs et al, 2017), we limited our analysis to samples harbouring < 1 copy of a housekeeping gene (B2M) to minimise the perceived contamination of cells or cellular debris in the ventricular CSF (vCSF); reducing our cohort to 14 PMS cases (38%) and 25 controls (58%)
Using these criteria we identified a significant reduction of vCSF ccf-mitochondrial DNA (mtDNA) level in PMS cases compared to controls (Wilcoxon Ranked Sum Test p = .013, mean rank ccf-mtDNA in 14 PMS cases was 16.4 and in 25 controls was 26.9, Fig. 1a)
Summary
Progressive multiple sclerosis (PMS) is a chronic, inflammatory, demyelinating disorder with progressive neurodegeneration (Stadelmann, 2011). Inflammation is an inducer of neuronal damage which, with chronic demyelination, leads to loss of central nervous system (CNS) tissue. White matter demyelination is a cardinal hallmark of PMS, neuropathological studies indicate extensive axonal loss in the spinal cord tracts and synapses of the gray matter (Bjartmar et al, 2003; Jurgens et al, 2016). Mitochondrial dysfunction plays a direct role in demyelination, with mitochondrial structural changes, altered gene expression and mitochondrial enzyme activities observed in MS patients (Mao and Reddy, 2010a). Multiple deletions of mtDNA, typically indicative of primary mitochondrial disease, can be detected in the gray matter of MS cases (Campbell et al, 2011)
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