Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model.
The B05 transgenic SCA1 mice, expressing human ataxin-1 with an expanded polyglutamine tract in cerebellar Purkinje cells (PCs), recapitulate many pathological and behavioral characteristics of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1), including progressive ataxia and PC loss. We transplanted neural precursor cells (NPCs) derived from the subventricular zone of GFP-expressing adult mice into the cerebellar white matter of SCA1 mice when they showed absent (5 weeks), initial (13 weeks), and significant (24 weeks) PC loss. Only in mice with significant cell loss, grafted NPCs migrated into the cerebellar cortex. These animals showed improved motor skills compared with sham-treated controls. No grafted cell adopted the morphological and immunohistochemical characteristics of PCs, but the cerebellar cortex in NPC-grafted SCA1 mice had a significantly thicker molecular layer and more surviving PCs. Perforated patch-clamp recordings revealed a normalization of the PC basal membrane potential, which was abnormally depolarized in sham-treated animals. No significant increase in levels of several neurotrophic factors was observed, suggesting, along with morphological observation, that the neuroprotective effect of grafted NPCs was mediated by direct contact with the host PCs. We postulate that a similar neuroprotective effect of NPCs may be applicable to other cerebellar degenerative diseases.
Laboratory of Experimental Neurology and 2Laboratory of Neurophysiology, Brussels Free University (ULB), Brussels, Belgium.
Satyan
S
Chintawar
Raphael
R
Hourez
Ajay
A
Ravella
David
D
Gall
David
D
Orduz
Myriam
M
Rai
Don Patrick
DP
Bishop
Stefano
S
Geuna
Serge N
SN
Schiffmann
Massimo
M
Pandolfo
D053687:Adult Stem Cells / Q000502:physiology* / Q000637:transplantation; D000704:Analysis of Variance; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002465:Cell Movement / Q000502:physiology; D002552:Cerebral Ventricles / Q000166:cytology; D003712:Dendrites / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics; D020127:Recovery of Function / Q000502:physiology*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine