Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy

Abstract

A b s t r a c t Despite the current hypotheses about myelinic and astrocytic ion-dyshomeostasis underlying white (WM) and grey matter (GM) vacuolation in mitochondrial encephalopathies, there is a paucity of data on the exact mechanism of vacuole formation. To revisit the concepts of vacuole formation associated with mitochondrial dysfunction, we performed a comparative neuropathological analysis in Kearns-Sayre syndrome (KSS) and full-length peroxisome proliferator-activated receptor-g coactivator-1α (FL-PGC-1α)-deficient mice, a recently proposed morphological model of mitochondrial encephalopathies. Brain tissues from an individual with genetically proven KSS (22-year-old man) and aged

Pathology of mitochondria in MELAS syndrome: an ultrastructural study

“…Although this mutation is the most common genetic cause of MELAS, it may give rise to diagnostic problems. It is responsible for a wide phenotypic diversity and can also cause other mitochondrial encephalomyopathies with different spectra of clinical signs, e.g., myoclonic epilepsy and ragged-red fibres (MERRF), overlap syndrome MELAS/MERRF, Leigh syndrome (LS), chronic external ophthalmoplegia (CEO), and Kearns-Sayre syndrome (KSS) [17,24,25,26,27]. Another difficulty in identifying the genetic basis of MELAS is the fact that the disease can be caused by other less common genetic mutations in the mitochondrial DNA (mtDNA).…”

Neuropathological characterization of FL-PGC-1α-deficient mice – implications for mitochondrial encephalopathy

“…All these raised the possibility that at least a proportion of vacuoles previously considered to be localized within the neuropil might be situated also within WM structures. This prompted us to further explore and characterize the observed lesion profile in a systematic comparison of aged FL-PGC-1α -/-animals and a human brain with KSS by the use of further immunohistochemical and electron microscopic techniques, with a special focus on the origin of vacuoles [117]. …”

“…The caudate-putamen of FL-PGC-1α -/-mice is free of reactive astrogliosis (GFAP) even at 70-75 weeks of age, suggesting that this murine strain is not a model for HD, as it was previously suggested. Original publication in: [117].…”

“…Note the well-preserved axons dodging between multiple vacuoles (B), similarly to that seen in KSS (C). Original publication in: [117].…”

“…Oligodendroglial vacuoles have not been reported previously in mitochondrial encephalopathies, and their presence as a potential source of intramyelin vacuoles might underlie their focal appearance. Original publication in: [117].…”