Presenilin-1 (PSEN1) is a part of the gamma secretase complex. It has several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins, and beta catenin. Besides APP cleavage, PSEN1 can affect processes like Notch signaling, β-cadherin processing, and calcium metabolism [2]. The WNF, GxGD, and PALP motifs in PSEN1 may play significant roles in γ-secretase mechanisms [2]. PSEN1 has been extensively studied, especially in the context of neurodegeneration, and is an important causative factor for early onset Alzheimer's disease (EOAD) [2].

PSEN1 mutations are associated with diverse phenotypes. Beyond classical EOAD, they are found in atypical AD or non-AD phenotypes such as frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), spastic paraparesis (SP), and even non-neurodegenerative phenotypes like acne inversa and dilated cardiomyopathy [1]. For example, specific mutations like Leu113Pro, Leu226Phe, Met233Leu, and an Arg352 duplication were found in FTD patients, while Pro436Gln, Arg278Gln, and Pro284Leu mutations were reported in patients with motor dysfunctions [1]. In a Chinese pedigree, the PSEN1 p.G417S mutation caused early-onset parkinsonism with cognitive impairment [3]. Also, a novel PSEN1 (P284S) mutation was discovered in a Chinese family with early-onset AD, which showed extensive cerebral cortex and cerebellar Aβ deposition [4].

In conclusion, PSEN1 is a crucial component of the gamma-secretase complex with a significant impact on multiple biological processes and disease conditions. Studies on PSEN1, especially those involving its mutations, have revealed its role in a wide range of neurodegenerative and non-neurodegenerative diseases. Understanding PSEN1 through model-based research can provide insights into the pathogenesis of these diseases and potentially lead to new therapeutic strategies.

References:

1. Yang, Youngsoon, Bagyinszky, Eva, An, Seong Soo A. 2023. Presenilin-1 (PSEN1) Mutations: Clinical Phenotypes beyond Alzheimer's Disease. In International journal of molecular sciences, 24, . doi:10.3390/ijms24098417. https://pubmed.ncbi.nlm.nih.gov/37176125/

2. Bagaria, Jaya, Bagyinszky, Eva, An, Seong Soo A. 2022. Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. In International journal of molecular sciences, 23, . doi:10.3390/ijms231810970. https://pubmed.ncbi.nlm.nih.gov/36142879/

3. Jiang, Li, Qin, Yan, Zhao, Yu-Wen, Tang, Bei-Sha, Guo, Ji-Feng. 2022. PSEN1 G417S mutation in a Chinese pedigree causing early-onset parkinsonism with cognitive impairment. In Neurobiology of aging, 115, 70-76. doi:10.1016/j.neurobiolaging.2022.03.016. https://pubmed.ncbi.nlm.nih.gov/35489321/

4. Xia, Mingrong, Gao, Chenhao, Wang, Huayuan, Zang, Weizhou, Zhang, Jiewen. . Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid β-Protein Deposition. In Current Alzheimer research, 19, 523-529. doi:10.2174/1567205019666220718151357. https://pubmed.ncbi.nlm.nih.gov/35850649/