Previously, we reported that ATXN1 oligomers are the primary drivers of toxicity in Spinocerebellar ataxia type 1 (SCA1; Lasagna-Reeves et al., 2015). Here we report that polyQ ATXN1 oligomers can propagate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculation. Our data also show that targeting these oligomers with passive immunotherapy leads to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span. These findings provide evidence that oligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular oligomers can mildly modify disease phenotypes.
Bibliographical noteFunding Information:
We thank the members of the Zoghbi, Orr and Kayed laboratories for suggestions and discussions, and V Brandt for critical reading of the manuscript. This work was supported by a Howard Hughes Medical Institute Collaborative Innovation Awards grant, the Robert A and Renee E Belfer Family Foundation and grant NIH/NINDS R01 NS027699-17. The NIH/NINDS 3R01 NS027699-25S1 and 1K22NS092688-01 to CALR. MWCR gratefully acknowledges The Canadian Institutes of Health Research Fellowship (201210MFE-290072-173743). We also appreciate the assistance of the confocal microscopy and mouse behavioral cores of the Baylor College of Medicine (BCM) Intellectual and Developmental Disabilities Research Center (1U54 HD083092).