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The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus

BACKGROUND: The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine ho...

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Autores principales: Lee, Jun Yup, Harney, Dylan, Kwok, John, Larance, Mark, Don, Anthony Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882607/
https://www.ncbi.nlm.nih.gov/pubmed/36711721
http://dx.doi.org/10.21203/rs.3.rs-2392941/v1
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author Lee, Jun Yup
Harney, Dylan
Kwok, John
Larance, Mark
Don, Anthony Simon
author_facet Lee, Jun Yup
Harney, Dylan
Kwok, John
Larance, Mark
Don, Anthony Simon
author_sort Lee, Jun Yup
collection PubMed
description BACKGROUND: The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. METHODS: Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66–104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. RESULTS: Forty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. Transmembrane protein 106B (TMEM106B), a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with age was specific to carriers of the rs1990622-A allele in the TMEM106B gene that is associated with increased risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. CONCLUSIONS: Our study provides the first evidence that TMEM106B protein abundance is increased with brain ageing in humans, and the first evidence that the major TMEM106B dementia risk allele affects brain lipid homeostasis, with a clear effect on myelin lipid content. Our data implies that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.
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spelling pubmed-98826072023-01-28 The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus Lee, Jun Yup Harney, Dylan Kwok, John Larance, Mark Don, Anthony Simon Res Sq Article BACKGROUND: The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. METHODS: Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66–104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. RESULTS: Forty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. Transmembrane protein 106B (TMEM106B), a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with age was specific to carriers of the rs1990622-A allele in the TMEM106B gene that is associated with increased risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. CONCLUSIONS: Our study provides the first evidence that TMEM106B protein abundance is increased with brain ageing in humans, and the first evidence that the major TMEM106B dementia risk allele affects brain lipid homeostasis, with a clear effect on myelin lipid content. Our data implies that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism. American Journal Experts 2023-01-17 /pmc/articles/PMC9882607/ /pubmed/36711721 http://dx.doi.org/10.21203/rs.3.rs-2392941/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Lee, Jun Yup
Harney, Dylan
Kwok, John
Larance, Mark
Don, Anthony Simon
The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title_full The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title_fullStr The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title_full_unstemmed The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title_short The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus
title_sort major tmem106b dementia risk allele affects tmem106b protein levels and myelin lipid homeostasis in the ageing human hippocampus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882607/
https://www.ncbi.nlm.nih.gov/pubmed/36711721
http://dx.doi.org/10.21203/rs.3.rs-2392941/v1
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