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Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?

Stanga S, Lanni C, Govoni S, Uberti D, D'Orazi G, Racchi M - Aging (Albany NY) (2010)

Bottom Line: Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Italy.

ABSTRACT
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.

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Related in: MedlinePlus

APP metabolism: schematic representation of the non-amyloidogenic and amyloidogenic pathway.Here the 770 residue APP processing is schematized, even if the 695 and 751 transmembrane forms of APP exist. In the non-amyloidogenic pathway, α-secretase cleaves APP in the extracellular domain and releases soluble APPα into the extracellular space. Following this cleavage, a second enzymatic product, the C-terminal fragment (αCTF or C83), which can be a substrate for ɣ-secretase, yields a non-amyloidogenic 3 kDa fragment known as p3. In the amyloidogenic pathway Aβ is formed following cleavage by β and ɣ secretases, respectively. The cleavage of APP at the residue 1 of Aβ sequence results in a truncated form of sAPP (sAPPβ) and in a C-terminal fragment of 12 kDa (βCTF or C99). The final step in the amyloidogenic pathway is the cleavage of βCTF, to liberate Aβ by ɣ-secretase. Furthermore, in both the amyloidogenic and non-amyloidogenic pathways, the cleavage of C83 and C99 fragments by ɣ-secretase also results in the generation of C-terminal peptides of 57-58 residues, referred as APP intracellular domain (AICD).
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Figure 1: APP metabolism: schematic representation of the non-amyloidogenic and amyloidogenic pathway.Here the 770 residue APP processing is schematized, even if the 695 and 751 transmembrane forms of APP exist. In the non-amyloidogenic pathway, α-secretase cleaves APP in the extracellular domain and releases soluble APPα into the extracellular space. Following this cleavage, a second enzymatic product, the C-terminal fragment (αCTF or C83), which can be a substrate for ɣ-secretase, yields a non-amyloidogenic 3 kDa fragment known as p3. In the amyloidogenic pathway Aβ is formed following cleavage by β and ɣ secretases, respectively. The cleavage of APP at the residue 1 of Aβ sequence results in a truncated form of sAPP (sAPPβ) and in a C-terminal fragment of 12 kDa (βCTF or C99). The final step in the amyloidogenic pathway is the cleavage of βCTF, to liberate Aβ by ɣ-secretase. Furthermore, in both the amyloidogenic and non-amyloidogenic pathways, the cleavage of C83 and C99 fragments by ɣ-secretase also results in the generation of C-terminal peptides of 57-58 residues, referred as APP intracellular domain (AICD).

Mentions: Beta-amyloid in AD is the result of the proteolytic metabolism of APP, an integral cell membrane glycoprotein of 697-770 residues which is the substrate of three proteolytic enzymes in two alternative pathways mutually in equilibrium [6]. In the non-amyloidogenic pathway, a protease, named α-secretase, cleaves APP in the extracellular domain and releases the ectodomain of APP (soluble APPα) into the extracellular space, thus precluding Aβ formation. Otherwise, in the amyloidogenic pathway, Aβ is formed following cleavage by β and ɣ secretases, that cleave the N and C terminus of Aβ, respectively (Figure 1). The two main isoforms found in AD brains are Aβ 1-40 and Aβ 1-42. Physiologically the 40-amino-acid long peptide is the most abundant form [7-9], since the concentration of secreted Aβ 1-42 is about 10% that of Aβ 1-40 [10]. For these reasons, Aβ1-40 and Aβ1-42 may have different biological actions [11] and the ratio of their production may be altered in pathological conditions, such as in familial AD [12].


Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?

Stanga S, Lanni C, Govoni S, Uberti D, D'Orazi G, Racchi M - Aging (Albany NY) (2010)

APP metabolism: schematic representation of the non-amyloidogenic and amyloidogenic pathway.Here the 770 residue APP processing is schematized, even if the 695 and 751 transmembrane forms of APP exist. In the non-amyloidogenic pathway, α-secretase cleaves APP in the extracellular domain and releases soluble APPα into the extracellular space. Following this cleavage, a second enzymatic product, the C-terminal fragment (αCTF or C83), which can be a substrate for ɣ-secretase, yields a non-amyloidogenic 3 kDa fragment known as p3. In the amyloidogenic pathway Aβ is formed following cleavage by β and ɣ secretases, respectively. The cleavage of APP at the residue 1 of Aβ sequence results in a truncated form of sAPP (sAPPβ) and in a C-terminal fragment of 12 kDa (βCTF or C99). The final step in the amyloidogenic pathway is the cleavage of βCTF, to liberate Aβ by ɣ-secretase. Furthermore, in both the amyloidogenic and non-amyloidogenic pathways, the cleavage of C83 and C99 fragments by ɣ-secretase also results in the generation of C-terminal peptides of 57-58 residues, referred as APP intracellular domain (AICD).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984604&req=5

Figure 1: APP metabolism: schematic representation of the non-amyloidogenic and amyloidogenic pathway.Here the 770 residue APP processing is schematized, even if the 695 and 751 transmembrane forms of APP exist. In the non-amyloidogenic pathway, α-secretase cleaves APP in the extracellular domain and releases soluble APPα into the extracellular space. Following this cleavage, a second enzymatic product, the C-terminal fragment (αCTF or C83), which can be a substrate for ɣ-secretase, yields a non-amyloidogenic 3 kDa fragment known as p3. In the amyloidogenic pathway Aβ is formed following cleavage by β and ɣ secretases, respectively. The cleavage of APP at the residue 1 of Aβ sequence results in a truncated form of sAPP (sAPPβ) and in a C-terminal fragment of 12 kDa (βCTF or C99). The final step in the amyloidogenic pathway is the cleavage of βCTF, to liberate Aβ by ɣ-secretase. Furthermore, in both the amyloidogenic and non-amyloidogenic pathways, the cleavage of C83 and C99 fragments by ɣ-secretase also results in the generation of C-terminal peptides of 57-58 residues, referred as APP intracellular domain (AICD).
Mentions: Beta-amyloid in AD is the result of the proteolytic metabolism of APP, an integral cell membrane glycoprotein of 697-770 residues which is the substrate of three proteolytic enzymes in two alternative pathways mutually in equilibrium [6]. In the non-amyloidogenic pathway, a protease, named α-secretase, cleaves APP in the extracellular domain and releases the ectodomain of APP (soluble APPα) into the extracellular space, thus precluding Aβ formation. Otherwise, in the amyloidogenic pathway, Aβ is formed following cleavage by β and ɣ secretases, that cleave the N and C terminus of Aβ, respectively (Figure 1). The two main isoforms found in AD brains are Aβ 1-40 and Aβ 1-42. Physiologically the 40-amino-acid long peptide is the most abundant form [7-9], since the concentration of secreted Aβ 1-42 is about 10% that of Aβ 1-40 [10]. For these reasons, Aβ1-40 and Aβ1-42 may have different biological actions [11] and the ratio of their production may be altered in pathological conditions, such as in familial AD [12].

Bottom Line: Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Italy.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus