The role of POLG mutations in human disease

Abstract

Mitochondrial diseases due to mutations in the nuclear Polymerase gamma (POLG) gene, have emerged as a common group of disorders, collectively referred to as POLG-related disorders. POLG is responsible for mitochondrial DNA (mtDNA) replication and repair. Defects in POLG result in secondary mtDNA defects including mtDNA depletion and deletions, which result in respiratory chain deficiency in affected tissues. POLG-related disorders are characterised by phenotypic diversity with common neurological deficits such as epilepsy, which constitutes its predominant manifestation. Alpers’ syndrome is a severe form of POLG-related disorders and it is a rare, early-onset, progressive encephalohepatopathy characterised by: intractable seizures, developmental delay, ataxia, visual loss and liver dysfunction. It is particularly devastating as effective treatments do not currently exist, and little is known about its molecular pathophysiology downstream from POLG mutations. The aim of this work was to gain further insight into the pathogenesis of Alpers, through the characterisation of mitochondrial dysfunction in POLG-mutant fibroblasts, and neuropathological investigation of post-mortem brain tissue from affected patients. Fibroblast characterisation using quantitative methodologies, revealed no evidence of mitochondrial dysfunction in primary POLG-mutant fibroblasts derived from patients with Alpers. Neuropathological assessment of three cortical regions revealed extensive respiratory chain deficiencies in interneurons and to a lesser extent pyramidal neurons in patients with Alpers, which was associated with severe pyramidal neuron loss. A variable degree of astrogliosis, was also observed. Additionally, mtDNA depletion was found in tissue from adult patients with POLG-mutations as well as occasional mtDNA deletions. This study provides evidence that POLG mutations exert a tissue-specific effect in Alpers. Mitochondrial respiratory chain deficiencies in interneurons and pyramidal neurons, combined with extensive pyramidal neuron loss may result in altered neuronal dynamics and contribute to the underlying neuropathology and clinical manifestations of Alpers.