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

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.

Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype

“…Since several neuronal microtubule‐associated proteins and kinesins bind preferentially to polyglutamylated tubulin (Janke and Kneussel ), it is possible that the loss of Nna1 gene affects the integrity of the tubulin network and axonal transport, which may cause a deficiency in protein transport and ER stress followed by the activation of mitochondrial apoptotic pathway (Muñoz‐Castañeda et al . ). It is possible that PC is more vulnerable and that they are long projecting neurons with complex dendritic trees, which require bulk axonal and dendritic transport demanding more metabolic energy.…”

Tubulin post‐translational modifications control neuronal development and functions

“…The well-known Purkinje-cell degeneration (pcd) mice carries a mutation in CCP1 deglutamylase and accumulates abnormally glutamylated tubulin in the brain regions where degeneration is observed. This discovery highlights the crucial role played by polyglutamylation in neuronal survival (Munoz-Castaneda et al, 2018;Rogowski et al, 2010). Interestingly, degeneration of CCP1-deficient neurons can be rescued by knockout of the major brain polyglutamylase TTLL1 (Magiera et al, 2018).…”

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

“…Ccp1 À/À mice were described before (Munoz-Castaneda et al, 2018). pcd mice (BALB/cByJ-Agtpbp1 pcdÀ3J /J; www.jax.org/strain/ 003237) were obtained from the Jackson Laboratory.…”