Is presenilin a gamma secretase?
As mentioned earlier, presenilin mutations were first identified in connection with familial AD, and subsequent work established that presenilin is the catalytic component of the γ-secretase complex that produces Aβ.
What is gamma secretase made of?
γ-secretase is a high molecular weight complex minimally composed of four components: presenilins (PS), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2).
What does γ-secretase do?
γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aβ) peptides that form amyloid plaques, which contribute to Alzheimer’s disease (AD) pathogenesis.
How do some presenilin genes cause familial Alzheimer’s disease?
Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the γ-secretase complex, which affects several downstream signalling pathways.
How do gamma secretase inhibitors work?
Gamma secretase inhibitors (GSIs) are a class of drugs that gained attention during the past decade in cancer treatment. The use of GSIs for cancers is primarily based on the premise that GSIs act by inhibiting the cleavage of γ-secretase, which result in blocking Notch 1 signaling [272].
What is the role of gamma secretase enzyme that cleaves APP?
These four γ-secretase enzymes together generate an active and stable complex that cleaves APP at the end of the Aβ domain in APP. Inhibition of these enzymes redirects the amyloidogenic pathway toward the nonamyloidogenic pathway by reducing Aβ production.
What secretase inhibitors?
Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aβ, so its inhibition provides a valid target for the AD.
How does presenilin 2 cause Alzheimer’s disease?
The loss of function of presenilin causes incomplete digestion of the amyloid β-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease.
Which presenilin complex modulates γ-secretase activity?
TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature440: 1208–1212 [PubMed] [Google Scholar]
Is presenilin 1 loss associated with increased β-catenin signaling?
Loss of presenilin 1 is associated with enhanced β-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci98: 10863–10868 [PMC free article][PubMed] [Google Scholar]
What are presenilins and why do they matter?
Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD).
What is the role of the presenilin C-terminus in nicastrin binding?
Kaether C, Capell A, Edbauer D, Winkler E, Novak B, Steiner H, Haass C 2004. The presenilin C-terminus is required for ER-retention, nicastrin-binding and γ-secretase activity.
