Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: Clinical and molecular genetic study

Department of Neurology and Programme of Neurosciences, Biomedicum-Helsinki, Helsinki University, and Helsinki University Central Hospital, Helsinki, Finland.
The Lancet (Impact Factor: 45.22). 09/2004; 364(9437):875-82. DOI: 10.1016/S0140-6736(04)16983-3
Source: PubMed


Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinson's disease. However, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the gene sequence of POLG in patients with progressive external ophthalmoplegia and their healthy relatives.
In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET).
We recorded mutations in POLG in members of all seven families. Clinical assessment showed significant cosegregation of parkinsonism with POLG mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron loss. Post-mortem examination in two individuals showed loss of pigmented neurons and pigment phagocytosis in substantia nigra without Lewy bodies. Furthermore, most women with progressive external ophthalmoplegia had early menopause-before age 35 years. The POLG gene defect resulted in secondary accumulation of mtDNA deletions in patients' tissues.
Dysfunction of mitochondrial POLG causes a severe progressive multisystem disorder including parkinsonism and premature menopause, which are not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG mutations in our families suggests that when defective, this gene can underlie mendelian transmission of parkinsonism.
Awareness that mitochondrial POLG mutations can underlie parkinsonism is important for clinicians working in diagnosis of movement disorders, as well as for studies of the genetics of Parkinson's disease. Further, progressive external ophthalmoplegia with muscle weakness and neuropathy can mask symptoms of parkinsonism, and clinicians should pay special attention to detect and treat parkinsonism in those individuals.

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    • "SN neurons from autopsies of normal-aged people and PD patients harbor high levels of mutated mtDNA with largescale deletions that cause mitochondrial dysfunction (Bender et al., 2006; Kraytsberg et al., 2006). Furthermore, mitochondrial disease patients with mutations in polymerase g, the polymerase responsible for mtDNA replication, excessively accumulate mtDNA mutations and also have an increased risk of developing PD (Luoma et al., 2004; Reeve et al., 2013). The many links between mitochondrial dysfunction and the pathogenesis of PD stimulated interest in the role PINK1 plays in that organelle. "
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    ABSTRACT: Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · Neuron
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    • "Polymerase gamma (POLG) replicates and repairs mitochondrial DNA (mtDNA). Mutations in POLG, the gene encoding the catalytic subunit, are among the most common causes of mitochondrial disease1 and have been linked to ageing2 and neurodegeneration.3–6 POLG mutations cause a variety of clinical phenotypes, including devastating encephalopathy syndromes that affect both adults and children, and that range from infantile hepatocerebral disease (Alpers–Huttenlocher syndrome) to juvenile or adult onset disorders with progressive spinocerebellar ataxia and epilepsy, known as mitochondrial recessive ataxic syndrome or mitochondrial spinocerebellar ataxia and epilepsy (MSCAE).7–9 "
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    ABSTRACT: Objective Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using post-mortem tissue from a large number of patients.Methods Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls were studied employing a combination of histopathology, immunohistochemistry and molecular studies of microdissected neurons.ResultsThe primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and which showed massive neuronal loss.InterpretationPOLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to two distinct, but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014. © 2014 American Neurological Association
    Full-text · Article · May 2014 · Annals of Neurology
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    • "Mutations in the mitochondrial DNA (mtDNA) polymerase γ (POLG) cause variable neurological presentations such as Alpers–Huttenlocher syndrome (AHS) [6], ataxia neuropathy spectrum including the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS), sensory ataxia, neuropathy, dysarthria, ophthalmoplegia (SANDO) [7] and chronic progressive external ophthalmoplegia (CPEO) plus parkinsonism [8]. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and this observation provided a potential clue for unveiling, at least in part, the mitochondrial mechanisms behind VPA toxicity. "
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    ABSTRACT: Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.
    Full-text · Article · Mar 2014 · Molecular Genetics and Metabolism
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