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Pin 1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in A lzheimer's disease
Author(s) -
Ueberham Uwe,
Rohn Susanne,
Ueberham Elke,
Wodischeck Susanne,
Hilbrich Isabel,
Holzer Max,
Brückner Martina K.,
Gruschka Hildegard,
Arendt Thomas
Publication year - 2014
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12163
Subject(s) - smad , pin1 , microbiology and biotechnology , biology , phosphorylation , smad2 protein , subcellular localization , immunoprecipitation , cell culture , biochemistry , genetics , isomerase , cytoplasm , gene
Aims Neurodegeneration in A lzheimer's disease ( AD ) is characterized by pathological protein aggregates and inadequate activation of cell cycle regulating proteins. Recently, Smad proteins were identified to control the expression of AD relevant proteins such as APP , CDK 4 and CDK inhibitors, both critical regulators of cell cycle activation. This might indicate a central role for Smads in AD pathology where they show a substantial deficiency and disturbed subcellular distribution in neurones. Still, the mechanisms driving relocation and decrease of neuronal Smad in AD are not well understood. However, Pin 1, a peptidyl‐prolyl‐cis/trans‐isomerase, which allows isomerization of tau protein, was recently identified also controlling the fate of Smads . Here we analyse a possible role of Pin 1 for Smad disturbances in AD . Methods Multiple immunofluorescence labelling and confocal laser‐scanning microscopy were performed to examine the localization of Smad and Pin 1 in human control and AD hippocampi. Ectopic Pin 1 expression in neuronal cell cultures combined with W estern blot analysis and immunoprecipitation allowed studying Smad level and subcellular distribution. Luciferase reporter assays, electromobility shift, RNAi ‐technique and qRT ‐ PCR revealed a potential transcriptional impact of Smad on Pin 1 promoter. Results We report on a colocalization of phosphorylated Smad in AD with Pin 1. Pin 1 does not only affect Smad phosphorylation and stability but also regulates subcellular localization of Smad2 and supports its binding to phosphorylated tau protein. Smads , in turn, exert a negative feed‐back regulation on Pin 1. Conclusion Our data suggest both Smad proteins and Pin 1 to be elements of a vicious circle with potential pathogenetic significance in AD .