Inhibition of NF-κB signaling in IKKβF/F;LysM Cre mice causes motor deficits but does not alter pathogenesis of Spinocerebellar ataxia type 1

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.

Utility of LysM-cre and Cdh5-cre Driver Mice in Retinal and Brain Research: An Imaging Study Using tdTomato Reporter Mouse

“…4A, 4B, 4C). As previously reported, [26][27][28] we found strong Lys/td signal in brain neurons of adult mice (Figs. 4D, 4E, 4F).…”

“…The LysM promoter has been reported to be expressed in mouse brain and spinal cord neurons. [26][27][28] More specifically, it has been shown to be expressed in motor cortex neurons and their axons, as well as in neurons of the hippocampus, and the molecular and Purkinje cell layers of the cerebellum where it colocalized with parvalbumin, a marker of GABA-ergic interneurons. [26][27][28] In the retina, Lys/td colocalized with parvalbumin, which marks some ganglion as well as some amacrine cells.…”

“…[26][27][28] More specifically, it has been shown to be expressed in motor cortex neurons and their axons, as well as in neurons of the hippocampus, and the molecular and Purkinje cell layers of the cerebellum where it colocalized with parvalbumin, a marker of GABA-ergic interneurons. [26][27][28] In the retina, Lys/td colocalized with parvalbumin, which marks some ganglion as well as some amacrine cells. In addition to its antimicrobial and immune modulatory effects, 13 lysozyme has been shown to play a role in Alzheimer's disease by clearing β-amyloid aggregates.…”

“…Moreover, it has been reported recently that the LysM promoter is also expressed in brain neurons. [26][27][28] On the other hand, the Cdh5 gene encodes the calcium-dependent cell adhesion molecule, cadherin 5 (VE-cadherin), which is expressed in both endothelial cells and hematopoietic cells. 29 VE-cadherin is a major component of the endothelial cell adherens junction and plays an important role in vascular permeability and angiogenesis.…”

Glial Factors Regulating White Matter Development and Pathologies of the Cerebellum

“…Mutations in many different genes are known to cause the different types of spinocerebellar ataxias (SCA) [96]. Among the Spinocereberllar ataxias, type 1 (SCA1) is the best known autosomal dominant neurodegenerative disease caused by the abnormal expansion of CAG repeats in the coding region of Ataxin 1 gene [97]. Cvetanovic et al [98] described astrocytic and microglial activities as an underlying cause of SCA1 which is characterized by the loss of Purkinje neurons in the cerebellum.…”