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Validating a Model for CMT1X Encephalopathy to Evaluate the Efficacy of a Molecular Chaperone Modulator
Wang, Yunwanbin
Wang, Yunwanbin
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Abstract
X-linked Charcot-Marie-Tooth disease (CMT1X) is caused by a large number of mutations in the gap junction beta 1 (GBJ1) gene that encodes the gap junction (GJ) protein connexin 32 (Cx32). Although the common phenotype of Cx32 mutations is a peripheral neuropathy, evidence suggests acute central nervous system (CNS) dysfunction also presents in CMT1X patients due to mutations of GJs expressed by oligodendrocytes throughout the CNS. The presence of an intracellularly retained Cx32 mutant T55I-Cx32 induces ER stress typically under inflammatory conditions, further exacerbating pathological changes for CNS phenotypes in CMT1X. Previously, we have identified that modulating molecular chaperones using a small molecule neurotherapeutic called KU-596 may be beneficial for treating the peripheral neuropathy of CMT1X. To clarify if KU-596 could modulate the CNS dysfunction associated with certain Cx32 mutations, we validated a model of systemic inflammation initiated by lipopolysaccharide (LPS) injection to Cx32 null mice expressing the T55I-Cx32 mutation (T55I-Cx32def) that is associated with CNS phenotypes. Behavioral analysis showed impairment of motor performance in LPS treated T55I-Cx32def mice. Iba1 immunostaining indicated widespread inflammation in the CNS of LPS treated T55I-Cx32def mice with diffusely activated microglia. Novel object recognition test revealed potential cognitive deficits in mice that had CNS dysfunction. The expression of ER-stress marker PERK analyzed by immunoblot increased in LPS treated T55I-Cx32def mice. KU-596 therapy improved the LPS induced inflammatory response in the CNS of T55I-Cx32def mice but did not improve cognition. Thus, KU-596 therapy may decrease CNS inflammation but it is unclear if it may improve cognition.
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2021-08-31
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University of Kansas
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Pharmacology