Abstract
BackgroundPolyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1.MethodsTransgenic mouse model of SCA1, ATXN1[82Q] mice, and wild-type littermate controls were treated with PLX from 3 weeks of age. The effects of PLX on microglial density, astrogliosis, motor behavior, atrophy, and gene expression of Purkinje neurons were examined at 3 months of age.ResultsPLX treatment resulted in the elimination of 70–80% of microglia from the cerebellum of both wild-type and ATXN1[82Q] mice. Importantly, PLX ameliorated motor deficits in SCA1 mice. While we have not observed significant improvement in the atrophy or disease-associated gene expression changes in Purkinje neurons upon PLX treatment, we have detected reduced expression of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and increase in the protein levels of wild-type ataxin-1 and post-synaptic density protein 95 (PSD95) that may help improve PN function.ConclusionsA decrease in the number of microglia during an early stage of disease resulted in the amelioration of motor deficits in SCA1 mice.
Highlights
Polyglutamine expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis
To study the role of microglia in SCA1, we reduced their numbers by using the pharmacological inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling, which is essential for microglial survival
PLX treatment reduces microglia in the cerebella of ATXN1[82Q] mice We have previously demonstrated an increase in the density of microglia, microglial hypertrophy, and altered expression of pro-inflammatory genes during the early stages of disease in several SCA1 mouse lines [4]
Summary
Polyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Neuroinflammation, the brain’s response to injury, is associated with many neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington disease (HD), and spinocerebellar ataxia type 1 (SCA1) [1,2,3,4,5,6,7]. Emerging evidence suggests that neuroinflammation can actively contribute to disease pathogenesis [8,9,10,11], but its role in disease is complex and includes both amelioration and promotion of disease progression. In a reaction to brain injury, microglia undergo morphological and functional changes, including enlargement of cell bodies and thickening of their processes and increased expression of pro-inflammatory cytokines. There are studies that suggest activated microglia may be beneficial in these diseases [24,25,26,27,28,29,30,31]
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