Seminar

Neuronal death and neuronal rescue: a model of cytoskeleton instability underlying motor and olfactory impairments

Eduardo Weruaga, PhD

The PCD (Purkinje Cell Degeneration) mutation triggers in the mouse both a severe ataxia and hyposmia because of the deficiency of Ccp1 gene/protein expression (Cytosolic CarboxyPeptidase 1). This single mutation provokes the death of Purkinje cells, yielding on a complete de-structuration of the cerebellum. In parallel and later, the mutation also affects the olfactory bulb with a slow loss of mitral cells. Further, these neurodegenerative processes run with reactive gliosis, with equivalent progression in both scenarios. In wild type animals, the expression of Ccp1 in the cerebellum is higher than in the olfactory bulb, which indicates a bigger dependence of the enzyme in the former compared to maintain nerve tissue homeostasis. Indeed, the cytoskeleton is one target of CCP1: its correct working allows equilibrated dynamics of microtubules, to maintain the dendritic arbor and the survival of neurons. Hence, the dynamics of PCD microtubules is affected by PCD mutation. We have performed cell therapy to stop the neurodegeneration, doing bone marrow transplantation of healthy animals into PCD ones. The results in the olfactory system were successful: the bone marrow-derived cells slowed the neurodegeneration of mitral neurons with a recovery of olfaction. The motor function was also partially recovered, but the histological analyses revealed that the source of this improvement was the muscular system instead of the cerebellum, where Purkinje cells were no rescued. Conversely, we employed oleoylethanolamide as a neuroprotective drug that restored microtubule dynamics both in vitro and in vivo, and consequently ameliorated the cerebellar degeneration of the PCD mouse, as measured by both cognitive and affective behavioral tests. Current experiments are directed to combine both pharmacological and cell therapies looking for synergies and to increase the effectiveness of the treatment. Selected publications •Baltanás FC, Berciano MT, Valero J, Gómez C, Díaz D, Alonso JR, Lafarga M, Weruaga E (2013) Differential glial activation during the degeneration of Purkinje cells and mitral cells in PCD mutant mice. Glia, 61:254-72. •Baltanás FC, Casafont I, Weruaga E, Alonso JR, Berciano MT, Lafarga M (2011) Nucleolar disruption and Cajal body disassembly are nuclear hallmarks of DNA damage-induced neurodegeneration in Purkinje cells. Brain Pathol., 21:374–88. •Díaz D, Gómez C, Muñoz-Castañeda R, Baltanás FC, Alonso JR, Weruaga E (2013) The olfactory system as a puzzle: playing with its pieces. Anat. Rec., 296:1383-1400. •Díaz D, Lepousez G, Gheusi G, Alonso JR, Lledo P-M, Weruaga E (2012) Bone marrow cell transplantation restores olfaction in the degenerated olfactory bulb. J. Neurosci., 32:9053-8. •Díaz D, Muñoz-Castañeda R, Alonso JR, Weruaga E (2015) Bone marrow-derived stem cells and strategies for treatment of nervous system disorders: many protocols, and many results. The Neuroscientist, 21:637-52. •Díaz D, Recio JS, Weruaga E*, Alonso JR* (*e.c.; 2012). Mild cerebellar neurodegeneration of aged heterozygous PCD mice increases cell fusion of Purkinje and bone marrow-derived cells. Cell Transplant., 21:1595-1602. •Recio JS, Álvarez-Dolado M, Díaz D, Baltanás FC, Piquer M, Alonso JR, Weruaga E (2011) Bone marrow contributes simultaneously to different neural types in the central nervous system by different mechanisms of plasticity. Cell Transplant., 20:1179-92. •Recio JS, Weruaga E, Gómez C, Valero J, Briñón J, Alonso JR (2007) Changes in the connections of the main olfactory bulb after mitral cell selective neurodegeneration. J. Neurosci. Res., 85:2407-21.