This review synthesizes evidence that the serine protease HTRA1 regulates brain proteostasis, ECM remodeling, and signaling (TGF-β, Wnt, Notch), has both protective and pathogenic roles, interacts with ApoE and tau, and presents biomarker and therapeutic targeting opportunities, with relevance…

HTRA1 influences proteostasis, inflammation, and vascular/ECM integrity—mechanisms relevant to Parkinson’s pathobiology and drug targeting—so the review highlights a moderately actionable target space (including inhibitors and biomarkers), but it lacks direct, PD-specific links to core processes…

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.