TY - JOUR
T1 - Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neuropathological tau measures
AU - Valentino, Rebecca R.
AU - Tamvaka, Nikoleta
AU - Heckman, Michael G.
AU - Johnson, Patrick W.
AU - Soto-Beasley, Alexandra I.
AU - Walton, Ronald L.
AU - Koga, Shunsuke
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Ross, Owen A.
N1 - Funding Information:
We would like to thank the patients, donors, and caregivers who participated in this research, without who this work would not have been possible. We would like to acknowledge the continuous commitment, technical support and teamwork offered by Linda G. Rousseau, Virginia R. Phillips, and Monica Castanedes‑Casey for tissue characterization. This work was supported in part by; the Mayo Clinic Florida Tau Center WithOut Walls (NINDS U54‑NS100693); ‑ an American Parkinson Disease Association (APDA), Mayo Clinic Information and Referral Center, and an APDA Center for Advanced Research. Samples included in this study were clinical controls or brain donors to the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP and the Tau Consortium. RRV designed the genotype assays and performed all laboratory analysis whilst MGH conducted, and is responsible for, all statistical data analy‑ sis. OAR had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
OAR and DWD are both supported by NINDS Tau Center without Walls Program (U54‑NS100693) and NIH (UG3‑NS104095). OAR is supported by NIH (P50‑NS072187; R01‑NS078086; U54‑NS100693; U54‑NS110435), DOD (W81XWH‑17‑1‑0249) The Michael J. Fox Foundation, The Little Family Founda‑ tion, the Mayo Clinic Foundation, and the Center for Individualized Medicine. DWD receives research support from the NIH (P50‑AG016574; U54‑NS100693; P01‑AG003949), CurePSP, the Tau Consortium, and the Robert E. Jacoby Profes‑ sorship. ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegen‑ erative Diseases fund, and The Albertson Parkinson’s Research Foundation. SK is supported by a post‑doctoral fellowship from the Karin & Sten Mortstedt CBD Solutions AB.
PY - 2020/9/17
Y1 - 2020/9/17
N2 - 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, 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 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), 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.
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, 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 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), 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.
KW - Corticobasal degeneration
KW - Mitochondrial haplogroups
KW - Neuropathology
KW - Progressive supranuclear palsy
KW - Tauopathy
KW - mtDNA
UR - http://www.scopus.com/inward/record.url?scp=85091192904&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091192904&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-01035-z
DO - 10.1186/s40478-020-01035-z
M3 - Article
C2 - 32943110
AN - SCOPUS:85091192904
VL - 8
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
SN - 2051-5960
IS - 1
M1 - 162
ER -