Ataxin-1 oligomers induce local spread of pathology and decreasing them by passive immunization slows Spinocerebellar ataxia type 1 phenotypes
Cristian A Lasagna-Reeves,
Maxime WC Rousseaux,
Marcos J Guerrero-Munoz,
Luis Vilanova-Velez,
Jeehye Park,
Lauren See,
Paymaan Jafar-Nejad,
Ronald Richman,
Harry T Orr,
Rakez Kayed,
Huda Y Zoghbi
Affiliations
Cristian A Lasagna-Reeves
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Maxime WC Rousseaux
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Marcos J Guerrero-Munoz
Department of Neurology, University of Texas Medical Branch, Galveston, United States
Luis Vilanova-Velez
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Jeehye Park
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Lauren See
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Paymaan Jafar-Nejad
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
Ronald Richman
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
Harry T Orr
Institute for Translational Neuroscience, University of Minnesota, Minnesota, United States
Rakez Kayed
Department of Neurology, University of Texas Medical Branch, Galveston, United States
Huda Y Zoghbi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United states
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.
