Summary of Study ST002928

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001821. The data can be accessed directly via it's Project DOI: 10.21228/M8B725 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002928
Study TitleThe major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus
Study SummaryBackground: 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. Fibrillar C-terminal TMEM106B fragments were isolated using sarkosyl fractionation and quantified by immunoblotting. 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. TMEM106B, a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with ageing was specific to carriers of the rs1990622-A allele in the TMEM106B gene that increases risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Rs1990622-A was also associated with higher TMEM106B fibril content. 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 demonstrates that TMEM106B protein abundance is increased with brain ageing in humans, establishes that dementia risk allele rs1990622-A predisposes to TMEM106B fibril formation in the hippocampus, and provides the first evidence that rs1990622-A affects brain lipid homeostasis, particularly myelin lipids. Our data suggests that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.
Institute
University of Sydney
Last NameLee
First NameJUN YUP
AddressJohn Hopkins Dr, Camperdown NSW 2050
Emailjlee4934@uni.sydney.edu.au
Phone0401042970
Submit Date2023-07-18
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2023-11-05
Release Version1
JUN YUP Lee JUN YUP Lee
https://dx.doi.org/10.21228/M8B725
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id APOE genotype TMEM SNP
SA31792421e2/e2 A/G
SA31792534e2/e2 A/G
SA31792632e2/e3 A/G
SA31792769e2/e3 A/G
SA31792835e2/e3 A/G
SA31792960e2/e3 A/G
SA31793046e2/e3 A/G
SA31793180e2/e3 A/G
SA3179322e2/e3 A/G
SA31793329e2/e3 G/G
SA3179349e2/e3 G/G
SA31793559e2/e3 NA
SA31793645e2/e4 A/A
SA3179378e2/e4 A/G
SA31793853e2/e4 G/G
SA31793961e2/e4 G/G
SA31794030e3/e3 A/A
SA31794136e3/e3 A/A
SA31794250e3/e3 A/A
SA31794356e3/e3 A/A
SA31794437e3/e3 A/A
SA31794533e3/e3 A/A
SA31794662e3/e3 A/A
SA31794716e3/e3 A/A
SA31794813e3/e3 A/A
SA31794975e3/e3 A/A
SA31795076e3/e3 A/A
SA31795118e3/e3 A/A
SA31795271e3/e3 A/A
SA31795322e3/e3 A/A
SA31795467e3/e3 A/A
SA31795551e3/e3 A/G
SA31795678e3/e3 A/G
SA31795752e3/e3 A/G
SA31795864e3/e3 A/G
SA31795955e3/e3 A/G
SA31796048e3/e3 A/G
SA31796173e3/e3 A/G
SA31796258e3/e3 A/G
SA31796368e3/e3 A/G
SA31796474e3/e3 A/G
SA31796541e3/e3 A/G
SA31796638e3/e3 A/G
SA3179677e3/e3 A/G
SA31796847e3/e3 A/G
SA31796919e3/e3 A/G
SA3179706e3/e3 A/G
SA31797127e3/e3 A/G
SA31797212e3/e3 A/G
SA31797344e3/e3 A/G
SA3179745e3/e3 A/G
SA31797542e3/e3 A/G
SA31797657e3/e3 G/G
SA31797711e3/e3 G/G
SA31797820e3/e3 G/G
SA31797917e3/e3 G/G
SA31798066e3/e3 G/G
SA31798124e3/e3 G/G
SA31798215e3/e3 G/G
SA31798310e3/e3 G/G
SA31798426e3/e3 G/G
SA31798579e3/e3 G/G
SA31798677e3/e3 NA
SA31798731e3/e3 NA
SA31798823e3/e4 A/A
SA3179891e3/e4 A/A
SA31799070e3/e4 A/A
SA31799154e3/e4 A/G
SA31799249e3/e4 A/G
SA31799325e3/e4 A/G
SA31799463e3/e4 A/G
SA31799514e3/e4 A/G
SA31799639e3/e4 A/G
SA31799743e3/e4 G/G
SA31799828e3/e4 G/G
SA31799965e3/e4 G/G
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