Background: The TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome-wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD-TDP). However, the causal variant that drives the association has thus far remained elusive.
Methods: We generated long-read whole-genome sequencing data of 256 individuals, primarily from Dutch descent. We characterized SNPs and larger structural variants in the TMEM106B locus using de novo genome assembly.
Results: We identified an insertion of an AluYb8 retrotransposon in the 3' UTR of TMEM106B gene, that was in complete linkage with the TMEM106B risk-SNP. AluYb8 retrotransposons have the propensity to propagate through our genomes by utilising a 'copy-paste' mechanism, and once integrated can disrupt transcription and translation of nearby genes. However, propagation of retrotransposons can be suppressed by methylation of the insert and its surrounding regions. Indeed, we observed that the risk haplotype with the AluYb8 insertion, but not the protective haplotype, accumulated CpG islands over evolutionary time. Notably, we observed similar retrotransposon insertions in the 3' UTR of TMEM106B orthologs in non-primate species. This suggests a survival advantage, which may be explained by recent findings that TMEM106B is an entry-receptor for specific viruses in lung-tissue, such that SINE-mediated downregulation of TMEM106B may limit viral infection-load across species.
Conclusions: We speculate that AluYb8-mediated downregulation of TMEM106B may be protective at younger ages in lung tissues, but that at advanced ages its downregulation in the brain may contribute to increased risk of neurodegenerative diseases. Furthermore, next to the supression of AluYb8 activation by DNA methylation, it may also be suppressed by TDP-43, in its role in post-translational RNA-processing. This leads us to further speculate that age-related demethylation and age-related dysregulation of TDP-43 may result in a negative feedback loop that ultimately reduces the endolysosomal activity in cells. We argue that such a mechanism would explain why increased age is among the strongest risk factors of neurodegenerative diseases.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/alz.090857 | DOI Listing |
Int J Biol Macromol
January 2025
First Operating Room, The First Hospital of Jilin University, Changchun, China. Electronic address:
Background: Certain peripheral proteins are believed to be involved in the development of Alzheimer's disease (AD), but the roles of other new protein biomarkers are still unclear. Current treatments aim to manage symptoms, but they are not effective in stopping the progression of the disease. New drug targets are needed to prevent Alzheimer's disease.
View Article and Find Full Text PDFBackground: Inclusions of TAR DNA binding protein of 43kDa (TDP-43) constitute the main characteristic pathology in the majority (∼97%) of amyotrophic lateral sclerosis (ALS) cases and approximately 50% of patients with frontotemporal lobar degeneration (FTLD). TDP-43 is a nuclear RNA binding protein; however, in disease, it becomes hyperphosphorylated and/or insoluble, hindering its nuclear function in maintaining RNA homeostasis. Importantly, the incidence of TDP-43 proteinopathy extends to aging brains (LATE) and may be concomitant with Alzheimer's disease (AD) neuropathological changes (LATE/AD) in up to 70% of AD patients.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Amsterdam UMC, Amsterdam, Netherlands.
Background: The TMEM106B protein is critical for proper functioning of the endolysomal system, which is utilised by all cells to traffic and degrade molecular cargo. Genome-wide association studies identified a haplotype in the TMEM106B gene that is associated with increased risk for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with TAR DNA binding protein inclusions (FTLD-TDP). However, the causal variant that drives the association has thus far remained elusive.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
German Center for Neurodegenerative Diseases (DZNE), Munich, Bavaria, Germany.
Background: Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of California Irvine, Irvine, CA, USA.
Background: Anti- Aβ monoclonal antibodies are the first FDA-approved treatments for AD that slow cognitive decline and lower Aβ plaques. Our goal is to identify the epitope specificities of antibodies in human blood that are associated with AD and NC and determine the predicted protein targets of these antibodies.
Method: 101 AD (MMSE < 27) and 98 NC (MMSE > 27) serum samples were obtained from the UCI tissue repository.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!