Paul-Flechsig-Institut für Hirnforschung
 Universitätsmedizin Leipzig

The function of Smad proteins is not restricted to its important transcriptional activity

Smad proteins are well known as transctription factors transferring signals from receptors of the canonical TGFbeta/BMP-superpathway towards cell nuclei. They are strongly involved in both early and late brain development and maintainance of neuronal differenciation.

In healthy brain phosphorylated Smad molecules are constitutively localized in neuronal nuclei, while we could detect a massively disturbed subcellular distribution of phosphorylated Smads in brains of Alzheimer's disease patients.

It seems that a persisting nuclear localization of phosphorylated Smad2/3 is essentially involved in the maintainance of the neuronal differentiation state. We could show, that already in early ontogenetic phases an increase of nuclear Smad2 in neurons occurs and is maintained throughout the whole life. An experimentally caused reduction of cellular Smad concentration results in the induction of cdk4 protein expression, a key enzyme of cell cycle regulation. The Smad decline therefore models the observed activation of cell cycle proteins in neurons of AD patients and shows its contribution to the neuronal apoptosis in AD brain. Moreover, neuronal loss of Smad availability is mediated by Pin1, a peptidyl-prolyl cis/trans isomerase, which is detectable together with phosphorylated Smads in specific vesicular cytoplasmic compartments in AD neurons.

In the project we examine specific roles of Smad proteins for neuronal differentiation and dedifferentiation processes with special focus on neurodegeneration. The experimental approach combines a variety of molecularbiological, biochemical, cell biological and immunohistochemical methods.

References:

Ueberham U, Rohn S, Ueberham E, Wodischeck S, Hilbrich I, Holzer M, Brückner MK, Gruschka, H Arendt T. Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer´s disease. Neuropathology and Applied Neurobiology 2014 Dec;40(7):815-32.

Ueberham, U., and Arendt,T.  (2013). The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons, Trends in Cell Signaling Pathways in Neuronal Fate Decision, Dr Sabine Wislet-Gendebien (Ed.), ISBN: 978-953-51-1059-0, InTech, DOI: 10.5772/54532.

Ueberham U, Hilbrich I, Ueberham E, Rohn S, Glöckner P, Dietrich K, Brückner MK, Arendt T. Transcriptional control of Cdk4 by Smad proteins - implications for Alzheimer´s disease. Neurobiology of Aging. 2012 Mar12; 33(12):2827-2840.

Ueberham U, Ueberham E, Gruschka H, Arendt T. Altered subcellular location of phosphorylated Smads in Alzheimer's disease. European Journal of Neuroscience. 2006; 24: 2327-34.

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Paul-Flechsig-Institut für Hirnforschung