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Aging and disease    2017, Vol. 8 Issue (4) : 506-518     DOI: 10.14336/AD.2016.1120
Review |
P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?
Szybińska Aleksandra1,2, Leśniakx Leśniak3,*
1Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena St., 02-109 Warsaw, Poland
2Department of Neurodegenerative Disorders, Laboratory of Neurogenetics, Mossakowski Medical Research Center Polish Academy of Sciences, 5 Pawinskiego St. 02-106 Warsaw, Poland
3Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw Poland
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Abstract  

Neurodegenerative diseases are a heterogeneous, mostly age-associated group of disorders characterized by progressive neuronal loss, the most prevalent being Alzheimer disease. It is anticipated that, with continuously increasing life expectancy, these diseases will pose a serious social and health problem in the near feature. Meanwhile, however, their etiology remains largely obscure even though all possible novel clues are being thoroughly examined. In this regard, a concept has been proposed that p53, as a transcription factor controlling many vital cellular pathways including apoptosis, may contribute to neuronal death common to all neurodegenerative disorders. In this work, we review the research devoted to the possible role of p53 in the pathogenesis of these diseases. We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal regulatory ties existing between p53 and proteins commonly regarded as pathological hallmarks of these diseases, with the ultimate goal to identify the primary element of their pathogenesis.

Keywords p53      neurodegenerative diseases      Alzheimer disease      Parkinson disease      apoptosis      neuronal loss     
Corresponding Authors: Leśniakx Leśniak   
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these authors equally contributed to this work

Issue Date: 01 August 2017
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Szybińska Aleksandra
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Szybińska Aleksandra,Leśniakx Leśniak. P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?[J]. Aging and disease, 2017, 8(4): 506-518.
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http://www.aginganddisease.org/EN/10.14336/AD.2016.1120     OR     http://www.aginganddisease.org/EN/Y2017/V8/I4/506
Diseasep53-linked effects in neuronsRegulation of the level of ND-associated proteins by p53Modulation of p53 level/activity by ND associated proteins
AlzheimerDNA damage, activated stress response, apoptotic death of neurons [51-53]PS1 down-regulation [104-105]
GSK3β and phospho-tau upregulation [112]
PS2 - p53 upregulation [69]
PS1 - p53 down- regulation, mut PS1- p53 upregulation [68] nicastrin, Aph1, Pen2- p53 down-regulation [70-72] APP, Aβ42, AICD - p53 upregulation [50, 68]
ParkinsonApoptotic neuronal death [57-58]
Caspase3, Bax levels increase [55, 56]
parkin [106] and α-synuclein [94] upregulationα-synuclein, synphilin-1 - p53 down-regulation [69, 81]
parkin - p53 down- regulation, mut. parkin -p53 upregulation [84] DJ-1 - p53 down- regulation [87]
HuntingtonDNA damage, activated stress response, apoptotic neuronal death [60]Htt upregulation [39, 108]mut. Htt - p53 upregulation [40, 59]
Down syndromeapoptotic neuronal death Bax, GAP-43, Fas levels increase [44, 47]ETS2, Prep1 - p53 upregulation [96, 97]
ALSApoptotic neuronal death, Rb, Bax, Fas, caspase levels increase [64]
Altered p53 localization [63, 64, 65]
mut SOD1, mutated optineurin - p53 upregulation [66, 90, 98]
MSApoptotic neuronal death [67, 91]
Table 1  Involvement of p53 in neurodegenerative diseases.
Figure 1.  Simplified scheme of p53 involvement in neurodegenerative diseases

p53 level and activity in neurons can increase not only as a result of oxidative stress and DNA damage but also due to aberrant regulation of its expression by mutated or erroneously cleaved proteins involved in neurodegeneration. Increased expression and activation of p53 entails enhanced expression of genes responsible for apoptosis or/and cell cycle arrest and, in consequence, may trigger neuronal death.

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