Expanding the ocular envolvement in mitochondrial disorders
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Transcript of Expanding the ocular envolvement in mitochondrial disorders
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Expanding the ocular involvement in mitochondrial disorders
Prof. Valerio Carelli
Laboratorio di Neurogenetica
IRCCS Institute of Neurological Sciences of Bologna,Bellaria Hospital, Bologna, ItalyNeurology Unit, Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy
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Leber Hereditary Optic Neuropathy (mtDNA)
Dominant optic atrophy (OPA1)Recessive optic atrophyX-linked optic atrophy
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Mitochondrial “Fission/Fusion”: new phenotypes with old and new genes
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DOA “plus”In 2008 we reported eight patients from sixindependent families showing thatmutations in the OPA1 gene can also beresponsible for a syndromic form of DOAcharacterized by:
• optic atrophy• sensorineural deafness• ataxia• axonal sensory-motor polyneuropathy• chronic progressive external ophthalmoplegia - CPEO • mitochondrial myopathy with mtDNA multiple deletions
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Old genes, new phenotypes 1: OPA1 – CPEO, neurodegeneration (parkinsonism and
dementia) and mtDNA multiple deletions
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mtDNA multiple deletions in skeletal muscle
Increased basal autophagy in fibroblastsand increased fragmentation (fusion defect)
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Abnormal mitophagy in OPA1 mutant fibroblasts
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PARIS NEMO
EXPLORING the Pink1/Parkin/OPA1 connection
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OPAthies
Parkinsonism/Dementia
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DOA, DOA “plus”/CPEO - mtDNA multiple deletions
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Old genes, new phenotypes 2: AFG3L2/SCA28 – assembles with the paralogous Paraplegin protein (SPG7) to form the oligomeric mAAA protease complex involved in mitochondrial protein maturation and degradation - implicated in OPA1 processing
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Family 1 (Puglia – DOA)
Family 2 (Campania – DOA)
Two large Italian families with the same mutation in AFG3L2/SCA28 (exon 11, c.1385C>T, p.Arg462Val, unpublished results)
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Isolated dominant optic neuropathy (DOA)with heterozygous novel SPG7 missensemutation c.1232A>C (p.Asp411Ala)
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DOA, DOA “plus”/CPEO - mtDNA multiple deletions
DOA, CPEOmtDNA multiple deletions
DOA, CPEOmtDNA multiple deletions
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DOA and mtDNA multiple deletions
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New genes 1: SLC25A46 – a modified carrier protein recruited to the outer mitochondrial membrane, an UGO1-like protein
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Loss of function unexpectedly leads to increased mitochondrial connectivity
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Patient derived fibroblasts confirm the silencing experiments
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New genes 2: RTN4 Interacting Protein 1 – RTN4IP1a mitochondrial (outer membrane) ubiquinol
oxydo-reductase partner of RTN4 (NOGO), an ER protein involved in dendritogenesis/branching and
susceptibility to UV light
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Silencing of RTN4IP1 induced altered number and morphogenesis of mouse RGC dendrites
Loss of the altered protein and deficit of complex I and IV activities
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PANNELLO DI 36 GENI PER ATROFIE OTTICHE EREDITARIE
UOC CLINICA NEUROLOGICA, IRCCS ISTITUTO DELLE SCIENZE NEUROLOGICHE DI BOLOGNA, LABORATORIO DI NEUROBIOLOGIA, OSPEDALE BELLARIA, BOLOGNA
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ESPERIENZA RECENTE CON IL PANNELLO DIAGNOSTICO PER LE ATROFIE OTTICHE
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Nuclear allotopic expression of a mitochondrial recoded gene (ND4) targeted to mitochondria
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Thanks for your attention and to the many collaborators:• Alfredo A. Sadun, USC, Los Angeles• Rubens Belfort Jr, UNIFESP, Sao Paolo• Carla Giordano, University “La Sapienza”, Rome• Palmiro Cantatore, University of Bari, Bari• Anna Ghelli, University of Bologna, Bologna• Pio D’Adamo, University of Trieste, Trieste• Vamsi Mootha, Harvard, Boston• Massimo Zeviani, MRC, Cambridge• Patrick Chinnery and Patrick Yu-Wai-Man, • University of Newcastle, Newcastle• Piero Barboni, San Raffaele, Milano
• ………and my lab: