Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1

Topic: Brain proteins, microglia and lab models

Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase.

@article{nelson2007-17431506,
  author  = {Nelson, O. and Tu, H. and Lei, T. and Bentahir, M. and de Strooper, B. and Bezprozvanny, I.},
  title   = {{Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1}},
  journal = {The Journal of clinical investigation},
  year    = {2007},
  doi     = {10.1172/jci30447},
  pmid    = {17431506},
  url     = {https://doi.org/10.1172/jci30447}
}

Key findings

• In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD).
• Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by gamma-secretase.
• Recently, we discovered that presenilins also function as passive ER Ca(2+) leak channels.
• Here we used planar lipid bilayer reconstitution assays and Ca(2+) imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca(2+) leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants.

Why it matters

Using lipid bilayer assays and calcium imaging in cells lacking presenilin, this study found that familial Alzheimer's disease-linked mutations disrupt the ability of presenilin 1 to act as a passive calcium leak channel in the endoplasmic reticulum. This is a laboratory finding about a possible disease mechanism and does not establish a treatment or cure.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1172/jci30447
• PubMed: 17431506
• Original source →
• Free full text: Journal of Clinical Investigation →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease Human molecular genetics · 1998-01-01 · usefulness score 50/100 · Risk genes beyond APOE
• The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism Proceedings of the National Academy of Sciences of the United States of America · 2006-12-29 · usefulness score 49/100 · Lewy body dementia
• Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease EMBO reports · 2007-02-01 · usefulness score 49/100 · Risk genes beyond APOE

Later studies that cite this one

3 studies in the alzhub library list this one in their references.

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Related studies in Risk genes beyond APOE

• Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease Nature Medicine · 1996-08-01 · usefulness score 59/100
• Familial Alzheimer's disease presenilin-2 mutants affect Ca2+ homeostasis and brain network excitability Aging clinical and experimental research · 2019-10-12 · usefulness score 41/100
• The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue Proceedings of the National Academy of Sciences of the United States of America · 1997-03-01 · usefulness score 50/100
• PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis Autophagy · 2019-03-27 · usefulness score 45/100
• Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo Neuron · 1996-11-01 · usefulness score 36/100
• {beta}-Amyloid impairs AMPA receptor trafficking and function by reducing Ca2+/calmodulin-dependent protein kinase II synaptic distribution The Journal of biological chemistry · 2009-02-24 · usefulness score 45/100

Also tagged “precursor”

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• Complement receptor 1 coding variant p.Ser1610Thr in Alzheimer's disease and related endophenotypes Neurobiology of aging · 2013-04-10 · usefulness score 41/100 · Tau biomarkers

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• Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology 2004 · Risk genes beyond APOE
• Presenilin-1 Familial Alzheimer Mutations Impair γ-Secretase Cleavage of APP Through Stabilized Enzyme–Substrate Complex Formation 2025 · Risk genes beyond APOE
• A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease 2014 · Tau biomarkers
• Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40 2006 · Risk genes beyond APOE
• Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2 2010 · Brain tissue and pathology
• Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor 1997 · Digital health tools

More on Risk genes beyond APOE

• A review that covers this ground Familial Alzheimer's disease sustained by presenilin 2 mutations: systematic review of literature and genotype-phenotype correlation Neuroscience and biobehavioral reviews · 2014-03-02 · usefulness score 66/100
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