White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells
Open accessPreprint — published as 10.1096/fj.202400689rr · Paper page
Abstract
White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation. SUMMARY STATEMENT: TRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.
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- Authors
- Yeung, S. H.-S., Lee, R. H.-S., Cheng, G. W.-Y., Ma, I. W.-T., Kofler, J., Kent, C., Ma, F., Herrup, K., Fornage, M., Arai, K., & Tse, K.-H.
- Affiliations
- Hong Kong Polytechnic University (HK)
- University of Pittsburgh (US)
- The University of Texas Health Science Center at Houston (US)
- Harvard University (US)
- The University of Sydney (AU)
- Corresponding author
- Tse, Kai-Hei
- ORCID
- Venue
- The FASEB Journal
- Publisher
- openRxiv
- Published
- 2023-12-19
- Volume
- 38
- Issue
- 19
- Pages
- e70059-e70059
- ISSN
- 0892-6638 (ISSN-L)
- PMC
- PMC10769267
- OpenAlex
- W4402918093
- Cited by
- 10
- References
- 2
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- The FASEB Journal (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PolyU Institutional Research Archive (Hong Kong Polytechnic University) (publishedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Pennsylvania Department of State (4100087331)
- Leo and Anne Albert Charitable Trust (P0031546)
- Research Grants Council, University Grants Committee (GRF15101422)
- Hong Kong Polytechnic University (P0030307)
- National Health and Medical Research Council (GA29942)
- National Institute on Aging (P50AG005133, P50AG008012, R01AG024494, P30AG066468, R01AG069912)
- National Institute of Neurological Disorders and Stroke (RF1NS120922)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- white matter hyperintensities, TRIM47, autophagy, brain endothelial cells, E3 ubiquitin ligase, ULK1 phosphorylation, hypertension, cerebral vasculature, age-related dementia, autophagy inhibition
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