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The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida.

ABSTRACT: Mutations in the gene encoding the presenilin-1 protein (PSEN1) were first discovered to cause Alzheimer's disease (AD) 20 years ago. Since then more than 200 different pathogenic mutations have been reported, including a p.Gly206Ala founder mutation in the Hispanic population. Here we report mutation analysis of known AD genes in a cohort of 27 early-onset (age of onset ?65, age of death ?70) Hispanic patients ascertained in Florida. The PSEN1 p.Gly206Ala mutation was identified in 13 out of 27 patients (48.1%), emphasizing the importance of this specific mutation in the etiology of early-onset AD in this population. One other patient carried the known PSEN1 p.Gly378Val mutation. Genotyping of the PSEN1 p.Gly206Ala and p.Gly378Val mutations in 63 late-onset Hispanic AD patients did not identify additional mutation carriers. All p.Gly206Ala mutation carriers shared rare alleles at two microsatellite markers flanking PSEN1 supporting a common founder. This study confirms the p.Gly206Ala variant as a frequent cause of early onset AD in the Hispanic population and for the first time reports the high frequency of this mutation in Hispanics in Florida.

SUBMITTER: Ravenscroft TA

PROVIDER: S-EPMC4788736 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida.

Ravenscroft Thomas A TA Pottier Cyril C Murray Melissa E ME Baker Matt M Christopher Elizabeth E Levitch Denise D Brown Patricia H PH Barker Warren W Duara Ranjan R Greig-Custo Maria M Betancourt Ana A English Mara M Sun Xiaoyan X Ertekin-Taner Nilüfer N Graff-Radford Neill R NR Dickson Dennis W DW Rademakers Rosa R

American journal of neurodegenerative disease 20160301 1

Mutations in the gene encoding the presenilin-1 protein (PSEN1) were first discovered to cause Alzheimer's disease (AD) 20 years ago. Since then more than 200 different pathogenic mutations have been reported, including a p.Gly206Ala founder mutation in the Hispanic population. Here we report mutation analysis of known AD genes in a cohort of 27 early-onset (age of onset ≤65, age of death ≤70) Hispanic patients ascertained in Florida. The PSEN1 p.Gly206Ala mutation was identified in 13 out of 27 ...[more]

PMID: 27073747

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Project description:OBJECTIVES:Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (A?) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in ?-secretase complex, the mutations of PS1 gene cause the interference of ?-secretase activity and lead to the increased A?42 secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons. MATERIALS AND METHODS:Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC-derived neurons using Mito-tracker. RESULTS:We observed that both extracellular and intracellular A? levels were dramatically increased in the PS1-S170F iPSC-derived neurons, compared with the control iPSC-derived neurons. Furthermore, PS1-S170F iPSC-derived neurons showed high expression levels of p-Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1-S170F iPSC-derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion-related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission-related protein DRP1 (dynamin-related protein 1) in the PS1-S170F iPSC-derived neurons. We further observed the defects of autophagy-related clearance in the PS1-S170F iPSC-derived neurons. Finally, we demonstrated the levels of A? and p-Tau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor. CONCLUSIONS:Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.

Dataset Information

The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida.

Publications

The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida.

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