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The effects of two polymorphisms on p21cip1 function and their association with Alzheimer’s disease in a population of European descent

The effects of two polymorphisms on p21cip1 function and their association with Alzheimer’s disease in a population of European descent
The effects of two polymorphisms on p21cip1 function and their association with Alzheimer’s disease in a population of European descent
With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer’s disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer’s disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer’s disease and Parkinson’s disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson’s disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer’s disease, and Parkinson’s disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer’s disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.
1932-6203
1-23
Padmanabhan, Jaya
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Yates, Sharon C.
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Zafar, Amen
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Rabai, Erzsebet M.
87d87afe-6544-4555-8c66-9032f3429030
Foxall, James B.
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Nagy, Sheila
5f1328b1-aedb-40c2-b198-9ea7f09ba9e4
Morrison, Karen E.
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Clarke, Carl
25a03ef6-9ef6-429c-9180-5cbfa5504660
Esiri, Margaret M.
452f775a-14ac-4806-8896-e5b6268bb56d
Christie, Sharon
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Smith, A. David
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Nagy, Zsuzsanna
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Padmanabhan, Jaya
fbc6c29c-475c-4989-b148-0524b8bf407f
Yates, Sharon C.
beb1250b-6e35-4681-8b27-dc53b89f2c00
Zafar, Amen
01cfc82d-5098-4783-90c3-0979a2533292
Rabai, Erzsebet M.
87d87afe-6544-4555-8c66-9032f3429030
Foxall, James B.
3aad7581-fbe4-40e6-9602-d5aefb396b58
Nagy, Sheila
5f1328b1-aedb-40c2-b198-9ea7f09ba9e4
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Clarke, Carl
25a03ef6-9ef6-429c-9180-5cbfa5504660
Esiri, Margaret M.
452f775a-14ac-4806-8896-e5b6268bb56d
Christie, Sharon
e0510b21-84fd-4fa4-8444-208796a232d0
Smith, A. David
df633949-c1d9-461d-bb86-bceffa024adb
Nagy, Zsuzsanna
4b81c3ef-3613-48f5-90a8-bf512ea721a0

Padmanabhan, Jaya, Yates, Sharon C., Zafar, Amen, Rabai, Erzsebet M., Foxall, James B., Nagy, Sheila, Morrison, Karen E., Clarke, Carl, Esiri, Margaret M., Christie, Sharon, Smith, A. David and Nagy, Zsuzsanna (2015) The effects of two polymorphisms on p21cip1 function and their association with Alzheimer’s disease in a population of European descent. PLoS ONE, 10 (1), 1-23. (doi:10.1371/journal.pone.0114050). (PMID:25625488)

Record type: Article

Abstract

With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer’s disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer’s disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer’s disease and Parkinson’s disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson’s disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer’s disease, and Parkinson’s disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer’s disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration.

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Accepted/In Press date: 9 October 2014
Published date: 27 January 2015
Organisations: Medical Education

Identifiers

Local EPrints ID: 398185
URI: http://eprints.soton.ac.uk/id/eprint/398185
ISSN: 1932-6203
PURE UUID: 174fefb3-1a9a-49b1-b671-daa298e08fb8
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 20 Jul 2016 13:49
Last modified: 03 Dec 2019 01:32

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Contributors

Author: Jaya Padmanabhan
Author: Sharon C. Yates
Author: Amen Zafar
Author: Erzsebet M. Rabai
Author: James B. Foxall
Author: Sheila Nagy
Author: Carl Clarke
Author: Margaret M. Esiri
Author: Sharon Christie
Author: A. David Smith
Author: Zsuzsanna Nagy

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