{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:22:08Z","timestamp":1791685328814,"version":"4.3.4"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,6,14]],"date-time":"2014-06-14T00:00:00Z","timestamp":1402704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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\u2010related neurodegeneration using postmortem tissue from a large number of patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical information was available from all subjects. Formalin\u2010fixed and frozen brain tissue from 15 patients and 23 controls was studied employing a combination of histopathology, immunohistochemistry, and molecular studies of microdissected neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The 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\u2013deficient 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 that showed massive neuronal loss.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>POLG 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 2 distinct but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears to be related to the presence of epileptic seizures. Our findings offer an explanation of the acute\u2010on\u2010chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014;76:66\u201381<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24185","type":"journal-article","created":{"date-parts":[[2014,5,20]],"date-time":"2014-05-20T05:24:37Z","timestamp":1400563477000},"page":"66-81","source":"Crossref","is-referenced-by-count":92,"title":["Molecular pathogenesis of polymerase gamma\u2013related neurodegeneration"],"prefix":"10.1002","volume":"76","author":[{"given":"Charalampos","family":"Tzoulis","sequence":"first","affiliation":[{"name":"Department of Neurology Haukeland University Hospital Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gia Tuong","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Coxhead","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Mitochondrial Research Institute of Genetic Medicine Newcastle University Newcastle upon Tyne United Kingdom"},{"name":"National Institute for Health Research Newcastle Biomedical Research Centre in Ageing and Chronic Disease Newcastle University Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn","family":"Bertelsen","sequence":"additional","affiliation":[{"name":"Department of Pathology Haukeland University Hospital Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peer K.","family":"Lilleng","sequence":"additional","affiliation":[{"name":"Department of Pathology Haukeland University Hospital Bergen Norway"},{"name":"Gade Laboratory for Pathology Department of Clinical Medicine Haukeland University Hospital University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Novin","family":"Balafkan","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Payne","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Mitochondrial Research Institute of Genetic Medicine Newcastle University Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrvoje","family":"Miletic","sequence":"additional","affiliation":[{"name":"Department of Pathology Haukeland University Hospital Bergen Norway"},{"name":"Department of Biomedicine University of Bergen Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick F.","family":"Chinnery","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Mitochondrial Research Institute of Genetic 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