Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer’s Disease

Abstract

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer’s disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

“…In addition, the involvement of PSEN1 in multiple pathways regulating calcium homeostasis, Notch signaling, or beta-catenin stability, among others, causes PSEN1 mutations to impact other neurodegenerative but also non-neurodegenerative diseases [142,146], a fact that severely interfere with the design and development of new therapeutic avenues for AD based on PSEN1 level changes. As an example, in recent clinical trials for autosomal dominant AD, human carriers of PSEN1 mutations have been longitudinally assessed for Aβ42 and p-tau in CSF but not for APP or PSEN1/2 levels, together with clinical symptoms and imaging analysis as endpoints for drug efficacy evaluation [147].…”

The Unfolded Protein Response: A Double-Edged Sword for Brain Health

“…Disturbed MAM signaling has been associated with both Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases that are associated with ER stress [ 204 , 205 ]. Additionally, IP 3 R channels are regulated by the ER membrane presenilins that are also considered ER calcium leak channels [ 206 , 207 ], and mutations in the presenilins are associated with AD [ 208 , 209 , 210 , 211 ]. Although the role of presenilins in maintaining ER calcium homeostasis requires further study, some of the mutations in these proteins were shown to disturb UPR signaling [ 212 ].…”

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

“…Late-onset AD (LOAD) is a multifactorial syndrome that typically begins after age 65. PSEN1 mutations have also been discovered in some atypical AD variants as well as in FTD, DLB, and PD [35]. While a number of risk genes are linked to LOAD (i.e., APOE4e4), age and a long list of other risk factors (e.g., gender, socioeconomic and educational status, diabetes) are associated with it [33].…”