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PMID: 17158800 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 51 ·2006-12-19 ·Pages 19524-9

Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park MK, Di Paolo G, Chung S, Kim TW

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg2+ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP2 closely correlates with 42-residue amyloid beta-peptide (Abeta42) levels. Our data suggest that PIP2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Abeta42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP2 may offer a therapeutic approach in Alzheimer's disease.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amyloid beta-Peptides/metabolism Blotting, Western Cell Line Electrophysiology Humans Mutation/genetics Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/metabolism Presenilins/genetics Protein Serine-Threonine Kinases TRPM Cation Channels/metabolism
Chemicals
Amyloid beta-Peptides Presenilins TRPM Cation Channels Phosphotransferases (Alcohol Group Acceptor) phosphatidylinositol 4,5-biphosphate kinase Protein Serine-Threonine Kinases TRPM7 protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Landman Natalie
Doctoral Program in Neurobiology and Behavior, Columbia University Medical Center, New York, NY 10032, USA.
Jeong Soon Youn
Shin Sun Young
Voronov Sergey V
Serban Geo
Kang Min Suk
Park Myung Kyu
Di Paolo Gilbert
Chung Sungkwon
Kim Tae-Wan
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0604954103
Published
2006-12-19
Epub
2006-00-08
Pages
19524-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1748258
Subset
IM
Grants
NINDS NIH HHS · NS43467 · United States
NINDS NIH HHS · NS51186 · United States
NINDS NIH HHS · R01 NS043467 · United States
NINDS NIH HHS · F31 NS051186 · United States
NICHD NIH HHS · HD047733 · United States
NICHD NIH HHS · R21 HD047733 · United States
External Links
PubMed source DOI: 10.1073/pnas.0604954103 PMC Full Text View journal details
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