Shortfalls in the peptidyl-prolyl cis-trans isomerase protein Pin1 in neurons are associated with frontotemporal dementias.
The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.
Electron Microscope Division, The Sussex Centre for Advanced Microscopy, School of Life Sciences, University of Sussex, Brighton, UK. J.R.Thorpe@sussex.ac.uk
Julian R
JR
Thorpe
Sabrina
S
Mosaheb
Lida
L
Hashemzadeh-Bonehi
Nigel J
NJ
Cairns
John E
JE
Kay
Simon J
SJ
Morley
Stuart L
SL
Rulten
D000328:Adult; D000368:Aged; D001479:Basal Ganglia; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000172:deficiency*; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase