title: Microangiopathy in the cerebellum of patients with mitochondrial DNA disease.
abstract: Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood-brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood-brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.
authors.affiliation: The Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Nichola Z
authors.initials: NZ
authors.lastname: Lax
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.forename: Amy K
authors.initials: AK
authors.lastname: Reeve
authors.forename: Philippa D
authors.initials: PD
authors.lastname: Hepplewhite
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jaros
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: Doug M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D002561:Cerebrovascular Disorders / Q000150:complications*; D024141:Collagen Type IV / Q000378:metabolism; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009245:NADH Dehydrogenase / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D018272:Porins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024141:Collagen Type IV; D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D051272:Glucose Transporter Type 1; C098483:NADH dehydrogenase subunit 4; D018272:Porins; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human