An AluYb8 mobile element characterises the risk haplotype of the TMEM106B locus associated with neurodegeneration
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.
Authors
- Marc Hulsman (ORCID: https://orcid.org/0000-0002-9889-3606)
- Lydian Knoop
- Henne Holstege (ORCID: https://orcid.org/0000-0002-7688-3087)
- Marcel Reinders (ORCID: https://orcid.org/0000-0002-1148-1562)
- Sven J. van der Lee (ORCID: https://orcid.org/0000-0003-1606-8643)
- Leonard Petrucelli (ORCID: https://orcid.org/0000-0003-2959-129X)
- Jana Křížová (ORCID: https://orcid.org/0000-0003-1841-7341)
- Alex Salazar (ORCID: https://orcid.org/0000-0002-8453-8769)
- Markus Daμμe (ORCID: https://orcid.org/0000-0002-9699-9351)
- Sanduni Wijesekera
- Yolande A.L. Pijnenburg (ORCID: https://orcid.org/0000-0003-2464-1905)
- Niccoló Tesi (ORCID: https://orcid.org/0000-0002-1413-5091)
- Mikko Hiltunen
Institutions
- University of Eastern Finland (FI)
- WinnMed (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Mayo Clinic in Florida (US)
- Amsterdam University Medical Centers (NL)
- Delft University of Technology (NL)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1002/alz.090857
- Citations
- 1
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.37