Pin1: a therapeutic target in Alzheimer neurodegeneration.
In Alzheimer's disease, the peptidyl prolyl cis/trans isomerase Pin1 binds to phospho-Thr231 on Tau proteins and, hence, is found within degenerating neurons, where it is associated to the large amounts of abnormally phosphorylated Tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated Tau. In the present work, we investigated, both at the cellular and molecular levels, the role of Pin1 in Alzheimer's disease through the study of its interactions with phosphorylated Tau proteins. We also showed that in neuronal cells, Pin1 upregulates the expression of cyclin D1. This, in turn, could facilitate the transition from quiescence to the G1 phase (re-entry in cell cycle) in a neuron and, subsequently, neuronal dedifferentiation and apoptosis. The involvement of Pin1 in the G0/G1 transition in neurons points to its function as a good target for the development of new therapeutic strategies in neurodegenerative disorders.
Hamdane
Malika
M
INSERM U422, IMPRT, Place de Verdun, Lille, France.
Smet
Caroline
C
Sambo
Anne-Véronique
AV
Leroy
Arnaud
A
Wieruszeski
Jean-Michel
JM
Delobel
Patrice
P
Maurage
Claude-Alain
CA
Ghestem
Antoine
A
Wintjens
René
R
Bégard
Séverine
S
Sergeant
Nicolas
N
Delacourte
André
A
Horvath
Dragos
D
Landrieu
Isabelle
I
Lippens
Guy
G
Buée
Luc
L
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D013050:Spectrometry, Fluorescence; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D016875:tau Proteins; D019938:Cyclin D1; D010751:Phosphopyruvate Hydratase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C005134:juglone