Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Abstract

ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1

“…Instead, our data suggest that a late defect in complex I may account for the reduction of electron transport across the respiratory chain as evidenced by the decreased maximal respiration in mutant neurons and the reduction of complex I levels and activity. Functional changes in complex I were previously reported in fibroblasts with OPA1 haploinsufficiency18 or the p.G488R mutation9 and in models of acute OPA1 depletion, where respiratory efficiency was impaired when mitochondria were energized specifically with the complex I substrates, glutamate/malate 17. Therefore, in human iPSC‐derived neurons, OPA1 levels are important for the maintenance of oxidative phosphorylation, at least partly, by regulating the stability of complex I.…”

“…Our initial whole‐exome analysis did not identify a secondary mutation of known pathogenicity, but does not exclude the contribution of multiple minor genetic determinants such as effects on autophagy, which is activated in cells carrying a mutant OPA1 allele9, 25 or microtubule‐associated transport, which is important for axonal mitochondrial motility. This withstanding, our finding that key cellular phenotypes are reproduced in vitro suggests, for the first time, that syndromic disease may arise from genetic modifiers that exacerbate the mitochondrial defect, which, at least in dopaminergic neurons, manifested as OPA1‐mediated mitochondrial fragmentation.…”

OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology

“…Other rare associations of OPA1 mutations in adults have been reported with spastic paraplegia (Yu-Wai-Man et al, 2010a), with the multiple sclerosis-like syndrome (Yu-Wai-Man et al, 2010a;Verny et al, 2008), with the Behr-like syndrome (Marelli et al, 2011) and, more recently, with syndromic parkinsonism and dementia (Carelli et al, 2015a).…”

OPA1 processing in cell death and disease – the long and short of it

“…This optic neuropathy is characterized by a destruction of retinal ganglion cells and the optic nerve, resulting in progressive vision loss. Although OPA1 is highly expressed in the retina, it is broadly expressed throughout the body and this might reflect the multiple disorders that have presented themselves in patients harboring heterozygous mutations of OPA1, including deafness and dementia (Carelli et al, 2015). Until recently, all OPA1 mutations found in patients have been identified as heterozygous, with the only homozygous OPA1 mutation causing early-onset encephalomyopathy, cardiomyopathy and death during infancy (Spiegel et al, 2016).…”