PT  - JOURNAL ARTICLE
AU  - Rebecca R. Valentino
AU  - Nikoleta Tamvaka
AU  - Michael G. Heckman
AU  - Patrick W. Johnson
AU  - Alexandra I. Soto-Beasley
AU  - Ronald L. Walton
AU  - Shunsuke Koga
AU  - Ryan J. Uitti
AU  - Zbigniew K. Wszolek
AU  - Dennis W. Dickson
AU  - Owen A. Ross
TI  - Associations of Mitochondrial Genomic Variation with Corticobasal Degeneration, Progressive Supranuclear Palsy, and Neuropathological Tau Measures
AID  - 10.1101/2020.07.10.196097
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.10.196097
4099  - http://biorxiv.org/content/early/2020/07/11/2020.07.10.196097.short
4100  - http://biorxiv.org/content/early/2020/07/11/2020.07.10.196097.full
AB  - Mitochondrial health is important in ageing and dysfunctional oxidative phosphorylation (OXPHOS) accelerates ageing and influences neurodegeneration. Mitochondrial DNA (mtDNA) codes for vital OXPHOS subunits and mtDNA background has been associated with neurodegeneration; however, no study has characterised mtDNA variation in Progressive supranuclear palsy (PSP) or Corticobasal degeneration (CBD) risk or pathogenesis. In this case-control study, 916 (42.5% male) neurologically-healthy controls, 1051 (54.1% male) pathologically-confirmed PSP cases, and 173 (51.4% male) pathologically-confirmed CBD cases were assessed to determine how stable mtDNA polymorphisms, in the form of mtDNA haplogroups, were associated with risk of PSP, risk of CBD, age of PSP onset, PSP disease duration, and neuropathological tau pathology measures for neurofibrillary tangles (NFT), neuropil threads (NT), tufted astrocytes (TA), and oligodendroglial coiled bodies (CB). 767 PSP cases and 152 CBD cases had quantitative tau pathology scores. mtDNA was genotyped for 39 unique SNPs using Agena Bioscience iPlex technologies and mitochondrial haplogroups were defined to mitochondrial phylogeny. After adjustment for multiple testing, we observed a significant association with risk of CBD for mtDNA sub-haplogroup H4 (OR=4.49, P=0.001) and the HV/HV0a haplogroup was associated with a decreased severity of NT tau pathology in PSP cases (P=0.0023). Our study reports that mitochondrial genomic background may be associated with risk of CBD and may be influencing tau pathology measures in PSP. Replication of these findings will be important.Competing Interest StatementZKW serves as PI or Co-PI on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as Co-PI of the Mayo Clinic APDA Center for Advanced Research. All other authors declare that they have no competing interests. No competing interests are reported by other authors.List of abbreviationsPSPProgressive supranuclear palsyCBDCorticobasal degenerationNFTNeurofibrillary tanglesNTNeuropil threadsTATufted astrocytesCBOligodendroglial coiled bodiesPDParkinson’s diseaseADAlzheimer’s disease4RFour-repeat tau isoformROSReactive oxygen speciesOXPHOSOxidative phosphorylationmtDNAMitochondrial DNAnDNANuclear DNAMALDI-TOF MSMatrix-assisted laser desorption/ionization mass spectrometryOROdds ratioCIConfidence intervalMT-ND2NADH dehydrogenase subunit-2MT-CYBCytochrome-b subunit of complex IIImtSNPMitochondrial DNA single nucleotide polymorphism