Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer’s Disease

Abstract

Mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease (fAD). Since the first mutations in the PSEN1 gene were discovered more than 25 years ago, many postulated functions of PS1 have been investigated. The majority of earlier studies focused on its role as the catalytic component of the γ-secretase complex, which in concert with β site amyloid precursor protein cleaving enzyme 1 (BACE1), mediates the formation of Aβ from amyloid-β protein precursor (AβPP). Though mutant PS1 was originally considered to cause AD by promoting Aβ pathology through its protease function, it is now becoming clear that PS1 is a multifunctional protein involved in regulating membrane dynamics and protein trafficking. Therefore, through loss of these abilities, mutant PS1 has the potential to impair numerous cellular functions such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism. Impaired calcium signaling, vacuolar dysfunction, mitochondrial dysfunction, and increased ER stress, among other related membrane-dependent disturbances, have been considered critical to the development and progression of AD. Given that PS1 plays a key regulatory role in all these processes, this review will describe the role of PS1 in different cellular compartments and provide an integrated view of how PS1 dysregulation (due to mutations or other causes) could result in impairment of various cellular processes and result in a “multi-hit”, integrated pathological outcome that could contribute to the etiology of AD.

A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels

“…As such, presenilin 1 and 2 mutants form the main genetic risk factors for familial Alzheimer's disease (FAD). In addition to this function, presenilins perform various γ-secretase-independent roles, such as modulation of intracellular Ca 2+ handling [244][245][246][247][248].…”

Cross-Talking Pathways of Forkhead Box O1 (FOXO1) Are Involved in the Pathogenesis of Alzheimer’s Disease and Huntington’s Disease

“…In addition, reduced organelle synthesis in ER that degrades misfolded proteins is also closely associated with the development of neurodegenerative diseases [ 42 , 43 ]. It is reported that ER stress can be induced by mutations in the PSEN1 gene contributing consequently to dysfunctional lysosome synthesis, a cause potentially responsible for familial AD [ 44 ]. Therefore, these findings lend strong support to our notion that FOXO1 plays an essential role in protein processing and maturation and is closely associated with the pathology of proteotoxicity-related diseases such as AD and HD.…”

Differentially Expressed Circular RNAs in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease

“…Mutations in either gene cause early‐onset AD 58 and SNCA accumulation in Lewy bodies (LBs) in these patients 59 . Besides their established role in mediating the formation of Aβ peptide, more recently mutant PS1 has been shown to impair numerous cellular functions, such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism 60 . Interestingly, a novel PSEN1 mutation was recently identified as the likely cause for early‐onset parkinsonism 61 …”