Search Results (4)

The cerebellar cortex presents a repetitive structure, but the main projecting neurons of this tissue, the Purkinje cells, are not identical and behave differently to various types of injury. Common patterns of neurodegeneration exist, where certain Purkinje cells die earlier than others. By contrast, lobe X of the cerebellum is a particularly resistant structure, independently of the cerebellar disease or damage. However, the mechanisms underlying the survival capability of these especially resistant Purkinje cells are still unknown. In this work, we have used the Purkinje Cell Degeneration (PCD) mouse, a model of severe cerebellar degeneration that also reproduces the human disease called childhood-onset neurodegeneration with cerebellar atrophy, to study Purkinje cell resistance. After an exhaustive immunochemical analysis of the different subpopulations of Purkinje cells, the Heat Shock Protein 25 (HSP25) and its phosphorylated version HSP25-P-Ser15 were found to be especially induced in lobe X of PCD mice. As this protein has neuroprotective properties, it may be responsible for resistance against cerebellar neurodegeneration. Taking into account the constant resistance of lobe X, the use of HSP25 may lead to new possibilities for achieving natural protection both in cerebellum and in other brain structures, or even for developing future neuroprotective therapies. Full article

The cytoskeleton relies heavily on the dynamic nature of microtubules, regulated by post-translational modifications such as polyglutamylation and deglutamylation. Disruption of its internal balance, particularly through the absence of cytosolic carboxypeptidase 1 (CCP1), leads to cytoskeletal collapse and cell death. An example of this occurrence exists in the Purkinje Cell Degeneration (PCD) mouse, a direct animal model for childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) human disease. Both CONDCA patients and PCD mice suffer a dramatic degeneration of Purkinje cells. Intriguingly, lobe X appears less vulnerable to this insult. This study revealed in wild-type mice that lobe X expresses less Ccp1 compared to other lobes, correlating with its delayed degeneration in PCD mice. Further expression analysis of other deglutamylating enzymes (CCP4 and CCP6) and glutamylating enzymes (TTLL1) revealed distinctive patterns: Ccp4 showed minimal relevance in cerebellum, while Ccp6 displayed a compensatory increase during critical stages. Meanwhile, Ttll1 expression remained consistent across lobes, suggesting that the resistance of lobe X may be related to a more dynamic, hyperglutamylated cytoskeleton. Unraveling the neuroresistance mechanisms of Purkinje cells may help mitigate neuronal loss in CONDCA patients and may offer a glimmer of hope for alleviating the symptoms of other neurodegenerative diseases. Full article

In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed to identify an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). However, increasing the frequency of rhVEGF-B administration had a detrimental effect on Purkinje cell survival, suggesting an inverted U-shaped dose–response curve of this substance. Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes. Full article

Recent reports have identified rare, biallelic damaging variants of the AGTPBP1 gene that cause a novel and documented human disease known as childhood-onset neurodegeneration with cerebellar atrophy (CONDCA), linking loss of function of the AGTPBP1 protein to human neurodegenerative diseases. CONDCA patients exhibit progressive cognitive decline, ataxia, hypotonia or muscle weakness among other clinical features that may be fatal. Loss of AGTPBP1 in humans recapitulates the neurodegenerative course reported in a well-characterised murine animal model harbouring loss-of-function mutations in the AGTPBP1 gene. In particular, in the Purkinje cell degeneration (pcd) mouse model, mutations in AGTPBP1 lead to early cerebellar ataxia, which correlates with the massive loss of cerebellar Purkinje cells. In addition, neurodegeneration in the olfactory bulb, retina, thalamus and spinal cord were also reported. In addition to neurodegeneration, pcd mice show behavioural deficits such as cognitive decline. Here, we provide an overview of what is currently known about the structure and functional role of AGTPBP1 and discuss the various alterations in AGTPBP1 that cause neurodegeneration in the pcd mutant mouse and humans with CONDCA. The sequence of neuropathological events that occur in pcd mice and the mechanisms governing these neurodegenerative processes are also reported. Finally, we describe the therapeutic strategies that were applied in pcd mice and focus on the potential usefulness of pcd mice as a promising model for the development of new therapeutic strategies for clinical trials in humans, which may offer potential beneficial options for patients with AGTPBP1 mutation-related CONDCA. Full article