The PSEN1 gene, short for Presenilin 1, is fundamentally important to human cellular function and was discovered as a major genetic link to early-onset neurodegenerative disease. Located on human chromosome 14, this gene provides the instructions for creating the Presenilin 1 protein, a multi-pass transmembrane protein embedded within the cell’s internal membranes. The protein is involved in several signaling pathways, including those that govern cell fate and development.
PSEN1: Core Component of Gamma-Secretase
The Presenilin 1 protein functions as the catalytic subunit of a large, multi-component molecular machine known as gamma-secretase. This complex, composed of four distinct proteins, acts as a specialized intramembrane protease, essentially working like a pair of molecular scissors. Gamma-secretase is situated within the cell membrane and is responsible for cleaving, or cutting, a variety of proteins that span the membrane, a process called proteolysis.
This cleavage is a normal and necessary function, involved in important cellular processes like cell signaling and the proper development of tissues. One of the most recognized substrates of gamma-secretase is the Amyloid Precursor Protein (APP), a larger protein made in the brain. The precise cutting of APP is part of the regular processing of this molecule and results in the production of various small fragments, including the amyloid-beta ($\text{A}\beta$) peptides.
The Link to Early-Onset Alzheimer’s Disease
Mutations in the PSEN1 gene are the most frequent genetic cause of Familial Alzheimer’s Disease (FAD), a form of the disorder characterized by an unusually early age of onset. While the more common, sporadic form of Alzheimer’s typically begins after age 65, individuals with PSEN1 mutations often develop symptoms before this age, sometimes as early as their 30s or 40s. This distinct, early-onset form accounts for up to 70 percent of FAD cases linked to the three known causative genes.
The disease course associated with PSEN1 mutations is often aggressive, progressing more rapidly than the late-onset form. Clinical manifestations can include features such as spasticity and seizures, which are less common in sporadic Alzheimer’s.
How Mutations Alter Amyloid Processing
The mechanism by which PSEN1 mutations trigger the disease involves an alteration in the function of the gamma-secretase complex. Normally, the enzyme cuts the Amyloid Precursor Protein (APP) to produce several forms of amyloid-beta peptides, predominantly the shorter $\text{A}\beta 40$. When PSEN1 is mutated, the function of the gamma-secretase is skewed.
The mutated Presenilin 1 protein causes a relative increase in the production of the longer, highly toxic $\text{A}\beta 42$ peptide instead of properly producing $\text{A}\beta 40$. This shift results in an elevated $\text{A}\beta 42/\text{A}\beta 40$ ratio, which is the primary driver of pathology in these familial cases. The $\text{A}\beta 42$ peptide is significantly more hydrophobic and prone to misfolding, quickly clumping together to form the insoluble amyloid plaques characteristic of Alzheimer’s disease.
Inheritance and Genetic Counseling
The inheritance pattern of PSEN1-linked Alzheimer’s is Autosomal Dominant, meaning a person only needs to inherit one copy of the mutated gene from either parent to develop the disease. Because of this high penetrance, inheriting the mutation guarantees the disease will manifest, although the specific age of onset can vary slightly depending on the exact mutation and other genetic factors.
Genetic testing and counseling play an important role for individuals in these families, providing scientific clarity but also raising psychological and ethical questions. Counselors help individuals understand the 50 percent chance of passing the gene to their children and the lack of preventive treatments currently available. Decisions about presymptomatic testing are deeply personal, often involving discussions on mental health, life planning, and family dynamics.
Developing Treatments Based on PSEN1
Current therapeutic research is focused on targeting the dysfunctional gamma-secretase complex to correct the molecular error caused by PSEN1 mutations. One strategy involves the development of Gamma-Secretase Modulators (GSMs), which are designed to selectively shift the enzyme’s cutting preference away from the toxic $\text{A}\beta 42$ peptide and back toward the less harmful $\text{A}\beta 40$ form. Unlike early Gamma-Secretase Inhibitors (GSIs), which failed clinical trials due to severe side effects from broadly blocking the enzyme’s function on other necessary proteins like Notch, GSMs aim to fine-tune the enzyme’s activity without a complete shutdown.
This modulation approach addresses the core issue of the $\text{A}\beta 42/\text{A}\beta 40$ ratio while avoiding the toxicity of general inhibitors. Furthermore, gene-targeting therapies are being investigated in preclinical models. These include using CRISPR-Cas9 to correct the specific PSEN1 mutation or employing antisense oligonucleotides (ASOs) to silence the mutant gene’s expression.