Presenilin 2 is a protein with a complex role in human biology, recognized for its association with inherited, early-onset Alzheimer’s disease. Beyond this connection, it is involved in fundamental cellular processes necessary for normal cell function. Understanding this protein means exploring its genetic origins, its role in cellular machinery, and how alterations in its structure can lead to disease, offering insights into both neurodegeneration and basic cell biology.
The Presenilin 2 Gene and Protein
The instructions for building the presenilin 2 protein are encoded in the PSEN2 gene on chromosome 1. Through a process called alternative splicing, the cell can use sections of this gene in different combinations. This allows for the creation of different versions, or isoforms, of the protein. These isoforms are distributed differently throughout the body, with one appearing in a wide range of tissues, including the brain, heart, and liver.
The presenilin 2 protein is a transmembrane protein, meaning it is embedded within and passes through cellular membranes. It has nine membrane-spanning domains, allowing it to be positioned correctly within cellular membranes. The protein is primarily found in the membranes of the endoplasmic reticulum and the Golgi apparatus, which are key sites for protein and lipid synthesis. Its presence is particularly notable in neurons, the primary cells of the brain and nervous system.
Presenilin 2’s Role in Cellular Machinery
Presenilin 2 is a central component of a larger molecular machine called the gamma-secretase complex. This complex is a group of four distinct proteins that assemble to perform a specific task. Presenilin 2 functions as the catalytic subunit of this complex, meaning it is responsible for carrying out the primary chemical reaction of the enzyme. Its role is that of an aspartyl protease, an enzyme that cuts other proteins at specific points.
The gamma-secretase complex specializes in a unique form of protein cutting known as intramembrane proteolysis. This process involves cleaving other transmembrane proteins directly within the portion that is embedded in the cell membrane. Two of the most important targets for gamma-secretase are the Amyloid Precursor Protein (APP) and a protein called Notch. By cutting these substrates, the complex releases protein fragments that can then travel to other parts of the cell, such as the nucleus, to regulate gene expression.
Connection to Alzheimer’s Disease
The link between presenilin 2 and Alzheimer’s disease is specific to a rare, inherited form of the condition called early-onset familial Alzheimer’s disease (FAD). While mutations in the PSEN2 gene are a much rarer cause of FAD than those in its counterpart, PSEN1, they have profound consequences. Over 30 mutations in the PSEN2 gene have been identified in families with FAD. These mutations are typically small changes in the gene’s code, leading to a single amino acid substitution in the resulting protein.
These changes in the presenilin 2 protein alter its function within the gamma-secretase complex, affecting how it processes the Amyloid Precursor Protein (APP). Normally, gamma-secretase cleaves APP to produce amyloid-beta peptides of different lengths, most commonly a 40-amino-acid version (Aβ40). The disease-causing mutations cause a shift in this cutting process, leading to an increased production of a slightly longer, 42-amino-acid version of the peptide, known as Aβ42.
This increase in the ratio of Aβ42 to Aβ40 is a major event in the development of Alzheimer’s. The Aβ42 peptide is more prone to clumping together than Aβ40. This aggregation leads to the formation of amyloid plaques, which are one of the defining pathological hallmarks found in the brains of individuals with Alzheimer’s disease. The accumulation of these plaques is thought to contribute to the widespread death of neurons that underlies the cognitive decline seen in the disease.
Broader Physiological Roles and Other Implications
The functions of presenilin 2 extend beyond its role in Alzheimer’s disease. Its activity as part of the gamma-secretase complex is also necessary for the Notch signaling pathway. When gamma-secretase cleaves the Notch receptor, it releases a fragment that travels to the nucleus to control genes involved in cell development and communication. This pathway is fundamental during embryonic development and for tissue maintenance.
Another function of presenilin 2 is its involvement in regulating calcium levels within the cell. It has a role in managing the communication and physical connection between the endoplasmic reticulum (ER) and mitochondria. Presenilin 2 helps tether these two structures together, facilitating the efficient transfer of calcium ions from the ER, the cell’s main calcium storage site, to the mitochondria. This calcium exchange is important for mitochondrial energy production and overall cellular health.
Emerging research also points to presenilin 2’s involvement in other cellular processes. It may have a role in neuroinflammation by influencing the release of inflammatory molecules called cytokines from microglia, the immune cells of the brain. Additionally, some studies have connected certain PSEN2 mutations to conditions other than Alzheimer’s, including specific types of dementia and breast cancer.