Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

Abstract

Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy.

• Authors: Liliana S Mendonça, Clévio Nóbrega, Hirokazu Hirai, Brian K Kaspar, Luís Pereira de Almeida
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 2 Pg. 320-35 (Feb 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 25527827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Brain-Derived Neurotrophic Factor
• Receptors, Neurotransmitter

Topics

• Animals
• Ataxia (etiology, pathology, therapy)
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Differentiation
• Cell Separation
• Cells, Cultured
• Cerebellum (cytology)
• Machado-Joseph Disease (pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neural Stem Cells (transplantation)
• Neuritis (etiology, therapy)
• Psychomotor Performance
• Receptors, Neurotransmitter (metabolism)