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Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Distinct age-related pattern of mitochondrial somatic mutations across multiple sclerosis phenotypes
Federica Esposito1,2, Kaalindi Misra1, Francesca Doyle1
1Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Background:
Mitochondrial dysfunction has been proposed as a contributor to neurodegeneration in multiple sclerosis (MS). While the accumulation of somatic mitochondrial DNA (mtDNA) mutations with age is well documented in other neurodegenerative conditions, its role in MS progression remains largely unexplored. The aim of this study was to investigate the association between age and somatic mtDNA mutation burden in MS patients and evaluate whether any difference exists according to disease course.
Methods:
A total of 404 MS patients were recruited. Whole mtDNA was sequenced from blood-derived DNA using long-range PCR and the Illumina® Nextera XT kit. Somatic mutations were defined based on heteroplasmy levels between 1-5%. Linear regression models were used to assess the association between age and mutation rate.
Results:
We observed a significant age-dependent increase in low-frequency non-synonymous mtDNA mutations in MS. Analyses stratified by disease course revealed that this effect was substantially driven by PPMS patients (n = 238, P = 2.71 × 10-3), while no association was seen in RRMS (n = 155, P = 0.35), suggesting course-specific mitochondrial trajectories. Furthermore, fast-progressing patients showed a positive linear relationship between age and mtDNA mutation rate (P = 0.017), while slow-progressing ones showed an opposite trend (test for interaction P = 0.013).
Conclusions:
These findings support the existence of a differential age-related accumulation of somatic mtDNA mutations detected in blood across MS courses.
Insights
Somatic mitochondrial DNA (mtDNA) mutations increase with age in multiple sclerosis (MS) patients, particularly in primary progressive MS. This age-related mutation burden differs significantly based on MS disease course.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Mitochondrial dysfunction is implicated in neurodegeneration in multiple sclerosis (MS).
- The role of age-accumulated somatic mitochondrial DNA (mtDNA) mutations in MS progression is understudied.
- Investigating mtDNA mutation burden in relation to age and MS disease course is crucial.
Purpose of the Study:
- To examine the association between age and somatic mtDNA mutation burden in MS patients.
- To determine if this association varies across different MS disease courses.
Main Methods:
- Sequenced whole mtDNA from blood-derived DNA of 404 MS patients.
- Defined somatic mutations based on heteroplasmy levels (1-5%).
- Employed linear regression models to analyze age and mutation rate associations.
Main Results:
- A significant age-dependent increase in low-frequency non-synonymous mtDNA mutations was observed in MS.
- This age effect was primarily driven by patients with primary progressive MS (PPMS).
- Fast-progressing MS patients showed a positive age-mutation rate correlation, while slow-progressing patients exhibited an inverse trend.
Conclusions:
- Evidence supports differential age-related accumulation of somatic mtDNA mutations in blood across MS disease courses.
- Findings highlight distinct mitochondrial aging trajectories in different MS subtypes.
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