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.

• Keywords
• Cerebellum, Lurcher mice, Neurotransplantation, Olivocerebellar degeneration,
• MeSH
• Cerebellar Ataxia pathology   MeSH
• Disease Models, Animal * MeSH
• Cerebellum * pathology   MeSH
• Mice, Transgenic * MeSH
• Mice MeSH
• Brain Tissue Transplantation methods   MeSH
• Green Fluorescent Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• enhanced green fluorescent protein MeSH Browser
• Green Fluorescent Proteins MeSH

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.

• Keywords
• Genetics, Models, Murine, Non-murine, Pathogenesis, Spinocerebellar ataxias, Therapies, Translational,
• MeSH
• Consensus MeSH
• Quality of Life * MeSH
• Models, Animal MeSH
• Cerebellum pathology   MeSH
• Mice MeSH
• Spinocerebellar Ataxias * diagnosis   genetics   therapy   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article 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.

• Keywords
• Ataxias, Cerebellar reserve, Cerebellum, Neurotransplantation, Stem cells,
• MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Cerebellar Diseases therapy   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

For many degenerative cerebellar diseases, currently, no effective treatment that would substantially restore cerebellar functions is available. Neurotransplantation could be a promising therapy for such cases. Nevertheless, there are still severe limitations for routine clinical use. The aim of the work was to assess volume and morphology and functional impact on motor skills of an embryonic cerebellar graft injected in the form of cell suspension in Lurcher mutant and wild-type mice of the B6CBA and C3H strains after a 6-month survival period. The grafts survived in the majority of the mice. In both B6CBA and C3H Lurcher mice, most of the grafts were strictly delimited with no tendency to invade the host cerebellum, while in wild-type mice, graft-derived Purkinje cells colonized the host's cerebellum. In C3H Lurcher mice, but not in B6CBA Lurchers, the grafts had smaller volume than in their wild-type counterparts. C3H wild-type mice had significantly larger grafts than B6CBA wild-type mice. No positive effect of the transplantation on performance in the rotarod test was observed. The findings suggest that the niche of the Lurcher mutant cerebellum has a negative impact on integration of grafted cells. This factor seems to be limiting for specific functional effects of the transplantation therapy in this mouse model of cerebellar degeneration.

• Keywords
• Cerebellar degeneration, Cerebellum, Lurcher mouse, Purkinje cell, Transplantation,
• MeSH
• Species Specificity MeSH
• Longitudinal Studies MeSH
• Rotarod Performance Test MeSH
• Disease Models, Animal MeSH
• Motor Skills MeSH
• Cerebellum embryology   pathology   transplantation   MeSH
• Mice, Neurologic Mutants MeSH
• Mice, Inbred C3H MeSH
• Mice, Inbred CBA MeSH
• Mice, Transgenic MeSH
• Cerebellar Diseases pathology   physiopathology   therapy   MeSH
• Neurodegenerative Diseases pathology   physiopathology   therapy   MeSH
• Graft Survival * physiology   MeSH
• Brain Tissue Transplantation * MeSH
• Green Fluorescent Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• enhanced green fluorescent protein MeSH Browser
• Green Fluorescent Proteins MeSH

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.

• Keywords
• Cerebellum, Hereditary cerebellar degeneration, Neurotransplantation,
• Publication type
• Journal Article MeSH
• Review MeSH

Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum.

• Keywords
• Ataxia, Cerebellar transplantation, Gait analysis, Lurcher, Olivocerebellar degeneration,
• MeSH
• Time Factors MeSH
• Gait MeSH
• Rotarod Performance Test MeSH
• Cerebellum embryology   metabolism   transplantation   MeSH
• Brain-Derived Neurotrophic Factor metabolism   MeSH
• Multiple System Atrophy physiopathology   therapy   MeSH
• Mice, Neurologic Mutants MeSH
• Mice, Inbred C57BL MeSH
• Mice, Inbred CBA MeSH
• Mice, Transgenic MeSH
• Motor Activity MeSH
• Spinocerebellar Degenerations physiopathology   therapy   MeSH
• Fetal Tissue Transplantation methods   MeSH
• Brain Tissue Transplantation methods   MeSH
• Treatment Outcome MeSH
• Green Fluorescent Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• enhanced green fluorescent protein MeSH Browser
• Brain-Derived Neurotrophic Factor MeSH
• Green Fluorescent Proteins MeSH