Cerebellar extinction lesions can manifest themselves with cerebellar motor and cerebellar cognitive affective syndromes. For investigation of the functions of the cerebellum and the pathogenesis of cerebellar diseases, particularly hereditary neurodegenerative cerebellar ataxias, various cerebellar mutant mice are used. The Lurcher mouse is a model of selective olivocerebellar degeneration with early onset and rapid progress. These mice show both motor deficits as well as cognitive and behavioral changes i.e., pathological phenotype in the functional domains affected in cerebellar patients. Therefore, Lurcher mice might be considered as a tool to investigate the mechanisms of functional impairments caused by cerebellar degenerative diseases. There are, however, limitations due to the particular features of the neurodegenerative process and a lack of possibilities to examine some processes in mice. The main advantage of Lurcher mice would be the expected absence of significant neuropathologies outside the olivocerebellar system that modify the complex behavioral phenotype in less selective models. However, detailed examinations and further thorough validation of the model are needed to verify this assumption.

• Klíčová slova
• Ataxia, Cerebellar Cognitive Affective Syndrome, Cerebellum, Lurcher Mouse, Validity,
• MeSH
• cerebelární ataxie genetika   patofyziologie   patologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• mozeček patologie   patofyziologie   MeSH
• myši - mutanty neurologické MeSH
• myši MeSH
• nemoci mozečku * patologie   patofyziologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Substitution of lost neurons by neurotransplantation would be a possible management of advanced degenerative cerebellar ataxias in which insufficient cerebellar reserve remains. In this study, we examined the volume and structure of solid embryonic cerebellar grafts in adult Lurcher mice, a model of olivocerebellar degeneration, and their healthy littermates. Grafts taken from enhanced green fluorescent protein (EGFP)-positive embryos were injected into the cerebellum of host mice. Two or six months later, the brains were examined histologically. The grafts were identified according to the EGFP fluorescence in frozen sections and their volumes were estimated using the Cavalieri principle. For gross histological evaluation, graft-containing slices were processed using Nissl and hematoxylin-eosin staining. Adjustment of the volume estimation approach suggested that it is reasonable to use all sections without sampling, but that calculation of values for up to 20% of lost section using linear interpolation does not constitute substantial error. Mean graft volume was smaller in Lurchers than in healthy mice when examined 6 months after the transplantation. We observed almost no signs of graft destruction. In some cases, compact grafts disorganized the structure of the host's cerebellar cortex. In Lurchers, the grafts had a limited contact with the host's cerebellum. Also, graft size was of greater variability in Lurchers than in healthy mice. The results are in compliance with our previous findings that Lurcher phenotype-associated factors have a negative effect on graft development. These factors can hypothetically include cerebellar morphology, local tissue milieu, or systemic factors such as immune system abnormalities.

• Klíčová slova
• Cerebellum, Lurcher mice, Neurotransplantation, Olivocerebellar degeneration,
• MeSH
• cerebelární ataxie patologie   MeSH
• modely nemocí na zvířatech * MeSH
• mozeček * patologie   MeSH
• myši transgenní * MeSH
• myši MeSH
• transplantace mozkové tkáně metody   MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enhanced green fluorescent protein MeSH Prohlížeč
• zelené fluorescenční proteiny MeSH

Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene. The expanded CAG repeat is translated into a prolonged polyglutamine repeat in the ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results in degeneration of the cerebellum and brain stem. In the current study, a non-allele-specific ATXN3 silencing approach was investigated using artificial microRNAs engineered to target various regions of the ATXN3 gene (miATXN3). The miATXN3 candidates were screened in vitro based on their silencing efficacy on a luciferase (Luc) reporter co-expressing ATXN3. The three best miATXN3 candidates were further tested for target engagement and potential off-target activity in induced pluripotent stem cells (iPSCs) differentiated into frontal brain-like neurons and in a SCA3 knockin mouse model. Besides a strong reduction of ATXN3 mRNA and protein, small RNA sequencing revealed efficient guide strand processing without passenger strands being produced. We used different methods to predict alteration of off-target genes upon AAV5-miATXN3 treatment and found no evidence for unwanted effects. Furthermore, we demonstrated in a large animal model, the minipig, that intrathecal delivery of AAV5 can transduce the main areas affected in SCA3 patients. These results proved a strong basis to move forward to investigate distribution, efficacy, and safety of AAV5-miATXN3 in large animals.

• Publikační typ
• časopisecké články MeSH

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.

• Klíčová slova
• Ataxias, Cerebellar reserve, Cerebellum, Neurotransplantation, Stem cells,
• MeSH
• buněčná a tkáňová terapie metody   MeSH
• nemoci mozečku terapie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15-Vps34 complex and the Nischarin-Pak1 signaling hub in the development of the telencephalon.

• MeSH
• alkylační látky toxicita   MeSH
• atrofie chemicky indukované   genetika   patologie   MeSH
• autofagie účinky léků   genetika   MeSH
• embryo savčí MeSH
• ethylnitrosomočovina toxicita   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   patologie   MeSH
• mutace účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• neurony účinky léků   patologie   ultrastruktura   MeSH
• neurovývojové poruchy * chemicky indukované   diagnostické zobrazování   genetika   patologie   MeSH
• novorozená zvířata MeSH
• pohyb buněk účinky léků   genetika   MeSH
• signální transdukce účinky léků   genetika   MeSH
• vakuolární protonové ATPasy účinky léků   genetika   MeSH
• vývojová regulace genové exprese účinky léků   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkylační látky MeSH
• ethylnitrosomočovina MeSH
• vakuolární protonové ATPasy MeSH
• Vps50 protein, mouse MeSH Prohlížeč

Hereditary cerebellar degenerations are a heterogeneous group of diseases often having a detrimental impact on patients' quality of life. Unfortunately, no sufficiently effective causal therapy is available for human patients at present. There are several therapies that have been shown to affect the pathogenetic process and thereby to delay the progress of the disease in mouse models of cerebellar ataxias. The second experimental therapeutic approach for hereditary cerebellar ataxias is neurotransplantation. Grafted cells might provide an effect via delivery of a scarce neurotransmitter, substitution of lost cells if functionally integrated and rescue or trophic support of degenerating cells. The results of cerebellar transplantation research over the past 30 years are reviewed here and potential benefits and limitations of neurotransplantation therapy are discussed.

• Klíčová slova
• Cerebellum, Hereditary cerebellar degeneration, Neurotransplantation,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration.

• Klíčová slova
• Ataxia, Cerebellum, Neurotransplantation, Stem cell,
• MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nemoci mozečku komplikace   chirurgie   MeSH
• neurodegenerativní nemoci komplikace   chirurgie   MeSH
• transplantace kmenových buněk metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Ataxic mutant mice can be used to represent models of cerebellar degenerative disorders. They serve for investigation of cerebellar function, pathogenesis of degenerative processes as well as of therapeutic approaches. Lurcher, Hot-foot, Purkinje cell degeneration, Nervous, Staggerer, Weaver, Reeler, and Scrambler mouse models and mouse models of SCA1, SCA2, SCA3, SCA6, SCA7, SCA23, DRPLA, Niemann-Pick disease and Friedreich ataxia are reviewed with special regard to cerebellar pathology, pathogenesis, functional changes and possible therapeutic influences, if any. Finally, benefits and limitations of mouse models are discussed.

• Klíčová slova
• Ataxia, Cerebellum, Neurodegeneration,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH