Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neuropathological tau measures

Rebecca R Valentino,Ronald L Walton,Nikoleta Tamvaka,Ryan J Uitti,Alexandra I Soto-Beasley,Shunsuke Koga,Michael G Heckman,Dennis W Dickson,Patrick W Johnson,Owen A Ross,Zbigniew K Wszolek

doi:10.1186/s40478-020-01035-z

Rebecca R Valentino, Ronald L Walton + Show 9 more

Open Access

https://doi.org/10.1186/s40478-020-01035-z

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Abstract

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.

Highlights

Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD) are rare progressive neurodegenerative movement disorders [1, 2]
In analysis that was adjusted for age and sex, to remove possible confounding influences, and after correcting for multiple testing (P ≤ 0.0021 considered significant), there were no significant associations between individual Mitochondrial DNA (mtDNA) haplogroups and PSP risk
Associations of individual mtDNA haplogroups with tau pathology scores of coiled bodies (CB), neurofibrillary tangles (NFT), tufted astrocytes (TA), and neuropil threads (NT) in PSP and of CB, NFT, astrocytic plaques (AP), and NT in CBD are summarised in Tables 3 and 4, respectively

Summary

Introduction

Progressive supranuclear palsy (PSP) and Corticobasal degeneration (CBD) are rare progressive neurodegenerative movement disorders [1, 2]. Generally considered sporadic disorders, MAPT, which encodes microtubule associated protein tau, is consistently documented as a strong genetic risk factor for both PSP and CBD [13, 14], and genetic variation in MAPT influences tau pathology severity in PSP [15]. ROS is suggested to contribute to the accumulation of insoluble proteinaceous deposits, such as Lewy bodies in PD, and senile plaques and NFT in AD [23,24,25], and dysfunction of complex I in the oxidative phosphorylation (OXPHOS) system has been shown to accelerate 4R tau isoform formation in PSP cell lines [26] and is defective in the substantia nigra of PD patients [27, 28]

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