This paper by the Malter group elegantly demonstrates a signaling cascade initiated by soluble Aβ42 that leads to calcineurin activation and Pin1 inhibition, thereby negatively affecting dendritic spine health. These findings are interesting and significant for a number of reasons. The authors have convincingly clarified/addressed some previous contradictory findings about the role of Pin1 in dendritic spine health (Westmark et al., 2010; Antonelli et al., 2016). Furthermore, given the prominent feature of dendritic spine loss in Alzheimer’s disease, these results further support a pivotal role for Pin1 in protecting against age-dependent neurodegeneration in Alzheimer’s disease, which was originally identified in our laboratory (Lu et al., 1999; Liou et al., 2003; Lu and Zhou, 2007).
Furthermore, since Pin1 regulates amyloid precursor protein processing and Ab production (Pastorino et al., 2006), these results suggest the interesting possibility of a positive feedback mechanism during the development of Alzheimer’s, wherein age-dependent Pin1 inhibition increases amyloidogenic APP processing and Ab42 production, which then further inhibits Pin1, leading to dendritic spine loss and many other neurodegenerative changes. Last but not least, their findings that loss of Pin1 activity can be prevented by inhibition of calcineurin may have important therapeutic implications for treating Alzheimer’s disease. Since calcineurin inhibitors FK506 and cyclosporin A used in this study are immunosuppressive in nature, it might be more desirable to design and evaluate the efficacy of non-immunosuppressive calcineurin inhibitors for treating AD.
— Xiao Zhou is a co-author of this comment
References:
Westmark PR, Westmark CJ, Wang S, Levenson J, O'Riordan KJ, Burger C, Malter JS.
Pin1 and PKMzeta sequentially control dendritic protein synthesis.
Sci Signal. 2010 Mar 9;3(112):ra18.
PubMed.
Antonelli R, De Filippo R, Middei S, Stancheva S, Pastore B, Ammassari-Teule M, Barberis A, Cherubini E, Zacchi P.
Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95.
J Neurosci. 2016 May 18;36(20):5437-47.
PubMed.
Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP.
The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.
Nature. 1999 Jun 24;399(6738):784-8.
PubMed.
Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP.
Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration.
Nature. 2003 Jul 31;424(6948):556-61.
PubMed.
Lu KP, Zhou XZ.
The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease.
Nat Rev Mol Cell Biol. 2007 Nov;8(11):904-16.
PubMed.
Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP.
The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.
Nature. 2006 Mar 23;440(7083):528-34.
PubMed.
Comments
Harvard Medical School
This paper by the Malter group elegantly demonstrates a signaling cascade initiated by soluble Aβ42 that leads to calcineurin activation and Pin1 inhibition, thereby negatively affecting dendritic spine health. These findings are interesting and significant for a number of reasons. The authors have convincingly clarified/addressed some previous contradictory findings about the role of Pin1 in dendritic spine health (Westmark et al., 2010; Antonelli et al., 2016). Furthermore, given the prominent feature of dendritic spine loss in Alzheimer’s disease, these results further support a pivotal role for Pin1 in protecting against age-dependent neurodegeneration in Alzheimer’s disease, which was originally identified in our laboratory (Lu et al., 1999; Liou et al., 2003; Lu and Zhou, 2007).
Furthermore, since Pin1 regulates amyloid precursor protein processing and Ab production (Pastorino et al., 2006), these results suggest the interesting possibility of a positive feedback mechanism during the development of Alzheimer’s, wherein age-dependent Pin1 inhibition increases amyloidogenic APP processing and Ab42 production, which then further inhibits Pin1, leading to dendritic spine loss and many other neurodegenerative changes. Last but not least, their findings that loss of Pin1 activity can be prevented by inhibition of calcineurin may have important therapeutic implications for treating Alzheimer’s disease. Since calcineurin inhibitors FK506 and cyclosporin A used in this study are immunosuppressive in nature, it might be more desirable to design and evaluate the efficacy of non-immunosuppressive calcineurin inhibitors for treating AD.
— Xiao Zhou is a co-author of this comment
References:
Westmark PR, Westmark CJ, Wang S, Levenson J, O'Riordan KJ, Burger C, Malter JS. Pin1 and PKMzeta sequentially control dendritic protein synthesis. Sci Signal. 2010 Mar 9;3(112):ra18. PubMed.
Antonelli R, De Filippo R, Middei S, Stancheva S, Pastore B, Ammassari-Teule M, Barberis A, Cherubini E, Zacchi P. Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95. J Neurosci. 2016 May 18;36(20):5437-47. PubMed.
Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999 Jun 24;399(6738):784-8. PubMed.
Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature. 2003 Jul 31;424(6948):556-61. PubMed.
Lu KP, Zhou XZ. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol. 2007 Nov;8(11):904-16. PubMed.
Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature. 2006 Mar 23;440(7083):528-34. PubMed.
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