title: Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration.
abstract: Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca(2+)-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca(2+) influx eliminated ectopic zones. Our findings in Car8(wdl) mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration.
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Department of Neuroscience, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: White
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Marife
authors.initials: M
authors.lastname: Arancillo
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Annesha
authors.initials: A
authors.lastname: King
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Miterko
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Samrawit A
authors.initials: SA
authors.lastname: Gebre
authors.affiliation: Department of Pathology & Immunology, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Department of Neuroscience, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, TX 77030, USA.
authors.forename: Roy V
authors.initials: RV
authors.lastname: Sillitoe
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D002753:Chlorzoxazone / Q000008:administration & dosage; D007858:Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014202:Tremor / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D002256:Carbonic Anhydrases
chemical_list: D014408:Biomarkers, Tumor; D002753:Chlorzoxazone; D009419:Nerve Tissue Proteins; D014446:Tyrosine 3-Monooxygenase; C512821:Car8 protein, mouse; D002256:Carbonic Anhydrases
keywords: Ataxia; Behavior; Cerebellum; In vivo electrophysiology; Neurodegeneration; Tremor