Dynamic rearrangements of microtubules induce growth or retraction of axons/dendrites in the developing nervous system and control neuroplasticity in the adult nervous system. Interestingly, signaling cascades used to control microtubule dynamics in neurons are used also in the dividing cells to control cell cycle.
It has been hypothesized, that in order to develop and continuously reshape synaptic connections, neurons must permanently withdraw from cell cycle, and that aberrant activation of mitotic kinases in adult neurons induces alteration of microtubule metabolism leading to neurodegeneration, e.g. in Alzheimer’s disease (AD). Peptidyl prolyl cis-trans isomerase Pin1 was originally discovered as a regulator of cell cycle, but it has been later shown to control many other cellular processes via its substrates. Microtubule associated proteins, e.g. tau, have been identified as important substrates of Pin1 and downregulation of Pin1 has been associated with AD in human patients and animal models. Thus, conformational stress resulting from defective Pin1 function could through deregulation of microtubule dynamics contribute to AD-related neurodegeneration.
We are characterizing the role of the conformational stress induced by Pin1 deregulation in AD pathogenesis in vivo using mouse AD models, and in vitro in primary neuron cultures.