Abstract
Spinocerebellar Ataxia type 1 (SCA1) is a fatal neurodegenerative genetic disease that is characterized by pronounced neuronal loss and gliosis in the cerebellum. We have previously demonstrated microglial activation, measured as an increase in microglial density in cerebellar cortex and an increase in the production of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), in the cerebellum of the ATXN1[82Q] transgenic mouse model of SCA1. To examine the role of activated state of microglia in SCA1, we used a Cre-Lox approach with IKKβF/F;LysM Cre mice intended to reduce inflammatory NF-κB signaling, selectively in microglia. ATXN1[82Q];IKKβF/F;LysM Cre mice showed reduced cerebellar microglial density and production of TNFα compared to ATXN1[82Q] mice, yet reducing NF-κB did not ameliorate motor impairments and cerebellar cellular pathologies. Unexpectedly, at 12 weeks of age, control IKKβF/F;LysM Cre mice showed motor deficits equal to ATXN1[82Q] mice that were dissociated from any obvious neurodegenerative changes in the cerebellum, but were rather associated with a developmental impairment that presented as a retention of climbing fiber synaptic terminals on the soma of Purkinje neurons. These results indicate that NF-κB signaling is required for increase in microglial numbers and TNF-α production in the cerebella of ATXN1[82Q] mouse model of SCA1. Furthermore, these results elucidate a novel role of canonical NF-κB signaling in pruning of surplus synapses on Purkinje neurons in the cerebellum during development.
Highlights
We have found that ATXN1[82Q];IKKβF/F;LysM Cre mice had decreased density of microglia and expression of Tumor necrosis factor alpha (TNFα) compared to ATXN1[82Q] littermates, suggesting that NF-κB pathway regulates early microglial recruitment and TNFα production in cerebella of Spinocerebellar ataxia type 1 (SCA1) mice
We deleted the catalytic subunit of IKKβ using a Cre-LoxP approach and produced the IKKβF/F;LysM Cre mouse line, in which the putative microglia and macrophage specific Lysozyme M promoter drives the expression of Cre-recombinase [45][48] to delete the exon 3 of IKKβ [44][49](S1 Fig)
We have found motor deficits in IKKβF/ F;LysM Cre mice that were dissociated from overt Purkinje cell degeneration but instead, associated with abnormal retention of climbing fiber synapses on Purkinje soma
Summary
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by the abnormal expansion of CAG repeats in the coding region of Ataxin (ATXN1). The CAG repeat is translated into an expanded polyglutamine (polyQ) track in the ATXN1 protein [2], which places SCA1 into the family of polyglutamine diseases that includes SCA 2, 3, 6, 7, 17, Kennedy disease, Huntington’s disease, and dentatorubropallidoluysian atrophy [3]. More than 39 uninterrupted CAG repeats in the ATXN1 gene causes SCA1, with the initial symptoms of ataxia, defined by movement and balance deficits, normally presenting in the patient’s mid-thirties. Motor deficits progressively worsen until premature death, commonly due to pulmonary compromise, 10–20 years from the disease onset [4]. There is no disease modifying therapy or cure for SCA1
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