Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1-4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.
Authors
- Jenni Lehtisalo (ORCID: https://orcid.org/0000-0002-8818-0848)
- Mari Takalo (ORCID: https://orcid.org/0000-0002-6609-1860)
- Marja Niiranen (ORCID: https://orcid.org/0000-0001-8674-020X)
- Mette Heiskanen (ORCID: https://orcid.org/0000-0003-1624-5240)
- Heli Jeskanen (ORCID: https://orcid.org/0009-0002-4783-7951)
- Henna Martiskainen (ORCID: https://orcid.org/0000-0003-2796-1859)
- Sami Heikkinen (ORCID: https://orcid.org/0000-0001-6976-2028)
- Teemu Kuulasmaa (ORCID: https://orcid.org/0000-0002-1795-7314)
- Roosa-Maria Willman (ORCID: https://orcid.org/0009-0009-5249-9038)
- Stephan A. Müller (ORCID: https://orcid.org/0000-0003-3414-307X)
- Sini-Pauliina Juopperi
- Inka Kervinen
- Rosa Sinisalo
- Viivi Pekkala (ORCID: https://orcid.org/0009-0008-6557-5784)
- Päivi Harju
- Petra Mäkinen
- Ana Galván del Rey
- Kirsi Saastamoinen
Institutions
- Broad Institute (US)
- Inserm (FR)
- University of Turku (FI)
- University of Eastern Finland (FI)
- Oulu University Hospital (FI)
- Institut Pasteur de Lille (FR)
- German Center for Neurodegenerative Diseases (DE)
- Turku University Hospital (FI)
- Karolinska Institutet (SE)
- Centre Hospitalier Universitaire de Lille (FR)
- Finnish Institute for Health and Welfare (FI)
- Massachusetts General Hospital (US)
- Kuopio University Hospital (FI)
- Turku PET Centre (FI)
- Munich Cluster for Systems Neurology (DE)
- Institute for Molecular Medicine Finland (FI)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Oulu (FI)
Publication Details
- Journal
- Molecular Neurodegeneration
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1186/s13024-025-00830-3
- Citations
- 4
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- Alzheimer's Association
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Biogen
- Celgene
- Itä-Suomen Yliopisto
- EU Joint Programme – Neurodegenerative Disease Research
- Maze Therapeutics
- Deutsche Forschungsgemeinschaft
- Academy of Finland
- Sigrid Juséliuksen Säätiö
- Biocenter Finland
- Business Finland
- Genentech
- Novartis Pharma
- European Regional Development Fund
- Janssen Biotech