In Vivo Phenotyping of Familial Parkinson's Disease with Human Induced Pluripotent Stem Cells: A Proof-of-Concept Study.
Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have previously developed a disease-in-a-dish model for familial PD using induced pluripotent stem cells (iPSCs) from two patients carrying the p.A53T α-synuclein (αSyn) mutation. By directed differentiation, we generated a model that displays disease-relevant phenotypes, including protein aggregation, compromised neurite outgrowth, axonal neuropathology and synaptic defects. Here we investigated the in vivo phenotypes of iPSCs, derived from one patient, after transplantation in a lesion mouse model established by unilateral intrastriatal 6-hydroxydopamine injection in the immunosuppressed NOD/SCID strain. Immunohistochemistry revealed that despite the disease-related characteristics that mutant cells displayed when maintained up to 70 days in vitro, they could survive and differentiate in vivo over a 12-week period. However, some differences were noted between patient-derived and control grafts, including a significant rise in αSyn immunoreactivity that might signal a first step towards pathology. Moreover, control-derived grafts appeared to integrate better than PD grafts within the host tissue extending projections that formed more contacts with host striatal neurons. Our data suggest that the distinct disease-related characteristics which p.A53T cells develop in vitro, may be attenuated or take longer to emerge in vivo after transplantation within the mouse brain. Further analysis of the phenotypes that patient cells acquire over longer periods of time as well as the use of multiple iPSC clones from different patients should extend our current proof-of-concept study and provide additional evidence for in vivo disease modeling.
['Zygogianni|Ourania|O|', 'Antoniou|Nasia|N|', 'Kalomoiri|Maria|M|', 'Kouroupi|Georgia|G|', 'Taoufik|Era|E|', 'Matsas|Rebecca|R|http://orcid.org/0000-0002-4027-348X']
D000818:Animals D001921:Brain D059290:Dopaminergic Neurons D006801:Humans D057026:Induced Pluripotent Stem Cells D008297:Male D016688:Mice, Inbred NOD D016513:Mice, SCID D009154:Mutation D010300:Parkinson Disease D010641:Phenotype D000075082:Proof of Concept Study D014183:Transplantation, Heterologous D051844:alpha-Synuclein
6-OHDA striatal lesions Alpha-synuclein Cell transplantation Dopaminergic neurons In vitro disease modeling Motor behavior