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Brain. 2015 Feb;138(Pt 2):320-35. doi: 10.1093/brain/awu352. Epub 2014 Dec 19.

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

Author information

1 CNC - Center for Neuroscience and Cell Biology, Vectors and Gene Therapy Group, Rua Larga, FMUC, University of Coimbra, 3004-504 Coimbra, Portugal.
2 Department of Neurophysiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
3 The Research Institute at Nationwide Children's Hospital, Ohio State University School of Medicine, Columbus, Ohio 43205, USA.
1 CNC - Center for Neuroscience and Cell Biology, Vectors and Gene Therapy Group, Rua Larga, FMUC, University of Coimbra, 3004-504 Coimbra, Portugal 4 Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal


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.


cerebellar neural stem cells transplantation; neuroinflammation; neuropathology and motor coordination; neurotrophic factors; spinocerebellar ataxia type 3

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