Toggle Main Menu Toggle Search

Open Access padlockePrints

Molecular neuropathology of MELAS: Level of heteroplasmy in individual neurones and evidence of extensive vascular involvement

Lookup NU author(s): Dr Susan Betts, Dr Evelyn Jaros, Emeritus Professor Robert Perry, Dr Andrew Schaefer, Professor Robert Taylor, Zeinab Abdel-All, Professor Robert Lightowlers, Professor Doug Turnbull

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients. © 2006 Blackwell Publishing Ltd.


Publication metadata

Author(s): Betts J, Jaros E, Perry RH, Schaefer AM, Taylor RW, Abdel-All Z, Lightowlers RN, Turnbull DM

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2006

Volume: 32

Issue: 4

Pages: 359-373

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/j.1365-2990.2006.00731.x

DOI: 10.1111/j.1365-2990.2006.00731.x

PubMed id: 16866982


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share