Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration.
The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles. Although mouse models have been created by overexpressing specific proteins including beta-amyloid precursor protein, presenilin and tau, no model has been generated by gene knockout. Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer's disease. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase. Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration; however, genetic evidence is lacking. Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioural deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.
Liou
Yih-Cherng
YC
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Sun
Anyang
A
Ryo
Akihide
A
Zhou
Xiao Zhen
XZ
Yu
Zhao-Xue
ZX
Huang
Han-Kuei
HK
Uchida
Takafumi
T
Bronson
Roderick
R
Bing
Guoying
G
Li
Xiaojiang
X
Hunter
Tony
T
Lu
Kun Ping
KP
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D020816:Amino Acid Motifs; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009043:Motor Activity / Q000502:physiology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018696:Neuroprotective Agents; D010750:Phosphoproteins; D010769:Phosphothreonine; D010768:Phosphoserine; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse