Cytoskeleton stability is essential for the integrity of the cerebellum and its motor- and affective-related behaviors

Rodrigo Muñoz-Castañeda,Annie Andrieux,José M Muñoz-Castañeda,Christophe Bosc,Eduardo Weruaga,David Díaz,Leticia Peris,José R Alonso,Carsten Janke,Marie-Jo Moutin

doi:10.1038/s41598-018-21470-2

Abstract

The cerebellum plays a key role in motor tasks, but its involvement in cognition is still being considered. Although there is an association of different psychiatric and cognitive disorders with cerebellar impairments, the lack of time-course studies has hindered the understanding of the involvement of cerebellum in cognitive and non-motor functions. Such association was here studied using the Purkinje Cell Degeneration mutant mouse, a model of selective and progressive cerebellar degeneration that lacks the cytosolic carboxypeptidase 1 (CCP1). The effects of the absence of this enzyme on the cerebellum of mutant mice were analyzed both in vitro and in vivo. These analyses were carried out longitudinally (throughout both the pre-neurodegenerative and neurodegenerative stages) and different motor and non-motor tests were performed. We demonstrate that the lack of CCP1 affects microtubule dynamics and flexibility, defects that contribute to the morphological alterations of the Purkinje cells (PCs), and to progressive cerebellar breakdown. Moreover, this degeneration led not only to motor defects but also to gradual cognitive impairments, directly related to the progression of cellular damage. Our findings confirm the cerebellar implication in non-motor tasks, where the formation of the healthy, typical PCs structure is necessary for normal cognitive and affective behavior.

Highlights

There is a consensus regarding the key role of the cerebellum in motor tasks, but its involvement in cognitive and affective functions is not well known[1,2]
We studied the microtubules of mouse embryonic fibroblasts (MEFs) lacking the cytosolic carboxypeptidase 1 (CCP1) enzyme, which we named Purkinje Cell Degeneration (PCD) microtubules (Fig. 1)
A temporal pattern is presented, characterizing the microtubule alterations observed in the PCD mouse, the progression of the cerebellar defects, and the influence of these alterations on motor and non-motor behaviors

Summary

Introduction

There is a consensus regarding the key role of the cerebellum in motor tasks, but its involvement in cognitive and affective functions is not well known[1,2]. The cerebellar destruction in different animal models, such as the Purkinje Cell Degeneration (PCD) mutant mouse[24,25] It is not known how microtubule dynamics shape cerebellar structure and function along postnatal development. The PCD mouse suffers a mutation in the Nna[1] gene, which encodes cytosolic carboxypeptidase 1 (CCP1), an enzyme responsible for the de-polyglutamylation of microtubules[24] This mutation induces the degeneration of the Purkinje cells (PCs) of the cerebellum, but its effect on microtubule dynamics and structure remains to be determined. Since neuronal degeneration of the PCD mouse is known to be associated with microtubule defects[32], this model allows us to understand, first, the effect of polyglutamylation on microtubules dynamics and structure and, second, how these alterations affect postnatal cognitive and social behaviors along the neurodegenerative process. We analyzed in these PCD mice the effect of progressive cerebellum degeneration on motor, cognitive, and social processes by means of an animal model lacking the CCP1 enzyme

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