Early stage of Spinocerebellar Ataxia Type 1 (SCA1) progression exhibits region- and cell-specific pathology and is partially ameliorated by Brain Derived Neurotrophic Factor (BDNF)

Abstract

AbstractSpinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, changes in affect, and premature lethality. Due to the severe cerebellar degeneration in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contribute to the symptoms of SCA1. Here, we investigate early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant brain regions including hippocampus and brain stem of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 globally.Our results indicate shared and brain region specific astrocyte pathology early in SCA1 preceding neuronal loss. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1, all of which are key for neuronal function in the hippocampus and brain stem. These gene expression changes did not correlate with classical astrogliosis. Neuronal and microglial numbers were largely unaltered at this early stage of SCA1 with the exception of cerebellar white matter, where we found significant reduction in microglial density, and the brain stem where we detected an increase in microglial cell counts.Brain-derived neurotrophic factor (BDNF) is a growth factor important for the survival and function of neurons with broad therapeutic potential for many brain diseases. We report here that BDNF expression is decreased in cerebellum and medulla of patients with SCA1. Moreover, we found that BDNF had dual effect on SCA1 and wild-type mice. Motor performance, strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus were ameliorated in BDNF-treated SCA1 mice and further enhanced in BDNF-treated wild-type mice. On the other hand, BDNF had a negative effect on memory recall and expression of homeostatic genes in the brain stem astrocytes both in wild-type and in SCA1 mice.