Repeat Diseases from SBMA to Motor Neuron Disease
Research indicates that transplantation of neural stem cells made from the part of the brain most affected in Machado-Joseph disease alleviates motor and neuropathological impairments in its mouse model and therefore may provide a therapy for this inherited ataxia.
Machado-Joseph disease/spinocerebellar ataxia type 3 is a genetic neurodegenerative disease causing enormous suffering without effective treatment. The disorder is caused by over - repetition of the trinucleotide cytosine-adenine-guanine (CAG) that translates into an overlong polyglutamine tract within the protein ataxin-3, which becomes aggregation - prone and toxic. Machado-Joseph disease patients exhibit severe impairments in gait and coordination of voluntary movement, and in articulation and swallowing . These impairments are associated with multiple neuropathological changes including mutant ataxin-3 aggregation in the patient’s brain. The condition is marked neuronal loss and atrophy of major neurons in the cerebellum, brainstem, and striatum.
Despite now having a greater understanding of its pathology, there is still no therapy able to modify the progression of the disease. Extensive neurodegeneration in symptomatic patients suggests an effective treatment of symptomatic Machado-Joseph disease patients may require cell replacement.
Neural stem cells (NSC) are self-renewing, multipotent cells with the ability to differentiate into all the neural cells (neurons, astrocytes , and oligodendrocytes) that constitute the nervous system. This work investigated for the first time whether transplantation of non mutant mouse cerebellar neural stem cells (cNSC) into the cerebellum of adult Machado-Joseph disease transgenic mice would alleviate motor coordination and neuropathological defects.
It was found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cNSC differentiated into neurons, astrocytes, and oligodendrocytes. Importantly, cNSC transplantation mediated a significant and robust alleviation of the motor behavior impairments in rotarod, foot-print and beam-walking tests as compared to control MJD mice injected with HBSS (2.1; 5.3; 1.7 and 2.9 fold improvement, respectively). This improvement correlated with a reduction of Machado-Joseph disease associated neuropathology, namely reduction of Purkinje cells loss, reduction of cellular layers shrinkage, and reduction of mutant ataxin-3 aggregates. Additionally, a significant reduction of cerebellar neuroinflammation markers and an increase of neurotrophic factors levels were observed, indicating that transplantation of cNSC also triggered important neuroprotective effects.
Thus, cNSC have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy. The next step is to evaluate whether neural stem cells generated by induction of patient fibroblasts can mediate similar benefits, opening the way for transplantation of neural stem cells generated from a patient’s own cells.