Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neur
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RESEARCH
Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neuropathological tau measures Rebecca R. Valentino1, Nikoleta Tamvaka1,2, Michael G. Heckman3, Patrick W. Johnson3, Alexandra I. Soto‑Beasley1, Ronald L. Walton1, Shunsuke Koga1, Ryan J. Uitti4, Zbigniew K. Wszolek4, Dennis W. Dickson1 and Owen A. Ross1,5,6*
Abstract Mitochondrial health is important in ageing and dysfunctional oxidative phosphorylation (OXPHOS) accelerates age‑ ing 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, 910 (42.6% male) neurologically-healthy controls, 1042 (54.1% male) pathologically-confirmed PSP cases, and 171 (52.0% male) pathologically-confirmed CBD cases were assessed to determine how stable mtDNA polymor‑ phisms, 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), astrocytic plaques (AP), and oligodendroglial coiled bodies (CB). 764 PSP cases and 150 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 an association with risk of CBD for mtDNA sub-haplogroup H4 (OR = 4.51, 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. Keywords: Progressive supranuclear palsy, Corticobasal degeneration, mtDNA, Mitochondrial haplogroups, Tauopathy, Neuropathology
Introduction Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD) are rare progressive neurodegenerative movement disorders [1, 2]. PSP typically presents *Correspondence: [email protected] 1 Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA Full list of author information is available at the end of the article
clinically with early falls, supranuclear vertical gaze palsy, parkinsonism, and dementia at about 65 years of age [3]. Individuals with CBD often present with progressive asymmetric rigidity and apraxia, loss of coordination, tremor, bradykinesia, akinesia, and occasionally alien limb syndrome [4, 5]. Both diseases have overlapping clinical symptoms with each other and other neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) [3, 6–8]. This
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