PSEN1

Presenilin 1 (PSEN1) is a protein that in humans is encoded by the PSEN1 gene on chromosome 14. It is one of the key proteins involved in the development of Alzheimer's disease, particularly in early-onset forms of the condition. PSEN1 is a part of the gamma-secretase complex, which plays a crucial role in the processing of the amyloid precursor protein (APP). Abnormal processing of APP can lead to the accumulation of amyloid beta (Aβ) peptides, a hallmark of Alzheimer's disease pathology.

Function

PSEN1 is integral to the function of the gamma-secretase complex, which is responsible for the intramembranous cleavage of several type I transmembrane proteins, including APP. The cleavage of APP by gamma-secretase results in the production of Aβ peptides of varying lengths. The 42-amino acid form of Aβ (Aβ42) is particularly prone to aggregation and is considered to be a major neurotoxic species in Alzheimer's disease. PSEN1 mutations can alter the activity of gamma-secretase, leading to increased production of Aβ42, thereby contributing to the pathogenesis of Alzheimer's disease.

Genetics

Mutations in the PSEN1 gene are the most common cause of autosomal dominant early-onset Alzheimer's disease. To date, over 200 mutations in the PSEN1 gene have been identified. These mutations are highly penetrant, meaning that individuals carrying a mutation in the PSEN1 gene have a very high risk of developing Alzheimer's disease, usually before the age of 65.

Clinical Significance

The identification of PSEN1 mutations in a patient or family can have significant implications for genetic counseling and disease management. Genetic testing for PSEN1 mutations is available and can be considered in the context of familial Alzheimer's disease or early-onset cases. However, the decision to undergo genetic testing should be made carefully, considering the potential psychological impact and the current lack of curative treatments for Alzheimer's disease.

Research Directions

Research on PSEN1 and its role in Alzheimer's disease continues to be a highly active area. Efforts are focused on understanding the precise mechanisms by which PSEN1 mutations lead to Alzheimer's disease, developing therapies that can modulate gamma-secretase activity without causing toxicity, and identifying biomarkers that can predict disease onset and progression in individuals with PSEN1 mutations.

See Also

• Alzheimer's disease
• Amyloid precursor protein
• Gamma-secretase
• Genetic testing