HTRA1 and brain disorders: A balancing act across neurodegeneration and repair
Year: 2026
Type: article
Abstract: High temperature requirement protein A1 (HTRA1) is a trypsin-like serine protease increasingly recognized as a central regulator of brain homeostasis. HTRA1 is broadly expressed in the brain, where it regulates proteostasis, extracellular matrix (ECM) remodeling, and important signaling pathways such as TGF-β, Wnt, and Notch. These functions are essential for maintaining blood-brain barrier integrity, supporting tissue repair, and restraining inflammation. HTRA1 is a double-edged sword, as both insufficient and excessive activity can lead to neurodegenerative and vascular pathology. Reduced HTRA1 levels are linked to ECM accumulation and vascular fibrosis, while elevated activity contributes to tissue breakdown, inflammation, and impaired repair. This dual role is implicated in a range of disorders, including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, small vessel disease, age-related macular degeneration, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We review recent insights into HTRA1's interactions with ApoE and tau, its roles in lipid and cytoskeletal regulation, and its modulation by inhibitors such as Macrophage Migration Inhibitory Factor. Finally, we explore its biomarker potential and therapeutic targeting strategies. Understanding the mechanisms behind HTRA1's shift from protective to pathological is crucial for developing targeted therapies that preserve its beneficial roles.
Source: Progress in Neurobiology
Institution: University of Southern Denmark
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
Funders: Scleroseforeningen, Jascha Fonden, Carlsbergfondet, Direktør Ejnar Jonasson Kaldet Johnsen og Hustrus Mindelegat, Karen A. Tolstrups Fond, Kong Christian den Tiendes Fond, Oda og Hans Svenningsens Fond, Aage og Johanne Louis-Hansens Fond, Minister Erna Hamiltons Legat for Videnskab og Kunst, Knud og Edith Eriksens Mindefond
OpenAlex ID: W7146946604