The HTRA1 gene provides instructions for creating HtrA serine peptidase 1, a protein found across many organs and tissues. This protein functions as a serine protease, an enzyme that breaks down other proteins into smaller fragments. Its presence is important for various biological processes within the body.
The HTRA1 Protein and Its Normal Functions
The HTRA1 protein, a serine protease, plays a role in maintaining the extracellular matrix, a network of molecules providing structural and biochemical support to surrounding cells. It helps break down various proteins within this matrix, contributing to tissue remodeling and integrity. HTRA1 also participates in cell signaling pathways.
One such pathway involves the transforming growth factor-beta (TGF-β) family of proteins. HTRA1 can bind to these TGF-β proteins, inhibiting their signaling. TGF-β proteins normally regulate cell growth, division, differentiation, movement, and programmed cell death (also known as apoptosis). TGF-β signaling is also involved in the formation of new blood vessels (a process called angiogenesis).
HTRA1 and Disease
Mutations or dysregulation of the HTRA1 gene have been linked to several human diseases, primarily affecting the brain and eyes.
Age-related Macular Degeneration (AMD) is a common condition associated with HTRA1, particularly a variant in the ARMS2/HTRA1 region on chromosome 10q26. AMD causes severe, irreversible central vision loss, affecting individuals over 65. This condition involves the progressive degeneration of the macula, the central part of the retina responsible for sharp, detailed vision.
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is another disease linked to HTRA1 mutations. This rare, inherited condition is characterized by non-hypertensive cerebral small-vessel disease, leading to early-onset stroke, progressive cognitive decline, and other features like alopecia and spondylosis. Heterozygous HTRA1 mutations have also been associated with an autosomal dominant form of cerebral small vessel disease, sometimes called CADASIL2, which presents with similar but often milder symptoms than CARASIL.
Cerebral Amyloid Angiopathy (CAA), an age-related condition characterized by the accumulation of amyloid-beta (Aβ) peptides in brain blood vessels, also shows a connection to HTRA1. CAA is a significant cause of intracerebral hemorrhage and cognitive decline, often co-occurring with Alzheimer’s disease. While not directly caused by HTRA1 mutations, studies indicate an accumulation of HTRA1 and its substrates within affected vessels of CAA patients, suggesting its involvement in disease pathology.
Understanding HTRA1’s Impact in Disease
The dysfunction of the HTRA1 protein contributes to disease development through various mechanisms, often involving its protease activity or interaction with signaling pathways.
In CARASIL, HTRA1 mutations lead to reduced protease activity or loss of the protein itself, disrupting normal regulation of the TGF-β signaling pathway. This impaired inhibition of TGF-β signaling contributes to abnormal thickening of small blood vessel walls in the brain, leading to strokes and leukoencephalopathy.
For Age-related Macular Degeneration (AMD), increased HTRA1 expression, particularly due to genetic variants in the 10q26 locus, is implicated. Overactive HTRA1 may excessively degrade components of Bruch’s membrane, a layer in the eye that supports the retina. This leads to damage and the formation of abnormal blood vessels in the choroid, a hallmark of wet AMD. This excessive proteolytic activity disrupts the extracellular matrix in the retina, contributing to vision loss.
In conditions like Cerebral Amyloid Angiopathy (CAA) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), even without direct HTRA1 mutations, there is evidence of impaired HTRA1 activity. In CADASIL, abnormal accumulation of Notch3 extracellular domain protein in blood vessel walls can sequester HTRA1, reducing functional availability and leading to substrate buildup. Similarly, in CAA, HTRA1 co-localizes with amyloid-beta deposits in brain capillaries, suggesting it might be trapped or its activity hindered by protein aggregates, contributing to vascular dysfunction and disease progression.