Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?
p53 transcriptional activity depends mainly on posttranslational modifications and protein/protein interaction. Another important mechanism that controls p53 function is its conformational stability since p53 is an intrinsically unstable protein. An altered conformational state of p53, independent from point mutations, has been reported in tissues from patients with Alzheimer's disease (AD), leading to an impaired and dysfunctional response to stressors. Recent evidence shows that one of the activators that induces p53 posttranslational modification and wild-type conformational stability is homeodomain interacting protein kinase 2 (HIPK2). Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity. Discovering the mechanisms of HIPK2 activation/inhibition and the ways to manipulate HIPK2 activity are an interesting option to affect several biological pathways, including those underlying AD. Soluble beta-amyloid peptides have recently been involved in HIPK2 degradation, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus, before triggering the amyloidogenic cascade. Here we discuss about these findings and the potential relevance of HIPK2 as a target for AD and highlight the existence of a novel amyloid-based mechanism in AD potentially leading to the survival of injured dysfunctional cells.
Stanga
Serena
S
Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Italy.
Lanni
Cristina
C
Govoni
Stefano
S
Uberti
Daniela
D
D'Orazi
Gabriella
G
Racchi
Marco
M
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000209:etiology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases