Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer’s Disease

Article type: Research Article

Authors: Liu, Collin Y.^a | Ohki, Yu^b | Tomita, Taisuke^b | Osawa, Satoko^b | Reed, Bruce R.^{c; d; 1} | Jagust, William^c | Van Berlo, Victoria^e | Jin, Lee-Way^c | Chui, Helena C.^a | Coppola, Giovanni^{e; f} | Ringman, John M.^{a; f; *}

Affiliations: [a] Alzheimer’s Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA | [b] Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan | [c] Alzheimer’s Disease Research Center, UC Davis, Davis, CA, USA | [d] Center for Scientific Review, National Institutes of Health, Bethesda, MD, USA | [e] Semel Institute at UCLA, Los Angeles, CA, USA | [f] Easton Center for Alzheimer’s Disease Research, UCLA, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: John M. Ringman, MD, MS, Helene and Lou Galen Endowed Professor of Clinical Neurology,Department of Neurology, Keck School of Medicine of USC, Center for the Health Professionals, 1540 Alcazar Street, Suite 209F, Los Angeles, CA 90089-0080, USA. Tel.: +1 323 442 0321; E-mail: [email protected].

Note: [1] Disclaimer: This article was prepared while Dr. Reed wasemployed at University of California, Davis. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government

Abstract: Background: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer’s disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. Objective: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. Methods: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. Results: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro. Conclusion: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.

Keywords: Autosomal dominant, familial Alzheimer’s disease, gamma-secretase, P88L, presenilin-1 (PSEN1), transmembrane domain, V89L

DOI: 10.3233/JAD-161203

Journal: Journal of Alzheimer's Disease, vol. 58, no. 4, pp. 1035-1041, 2017