Abstract
Huntington's Disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in huntingtin (htt) protein. The expansion leads to increased htt aggregation and toxicity. Factors that aid in the clearance of mutant huntingtin proteins should relieve the toxicity. We previously demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD. Here we tested whether overexpression of ubiquilin-1 delays or prevents neurodegeneration in R6/2 mice, a well-established model of HD. We generated transgenic mice overexpressing human ubiquilin-1 driven by the neuron-specific Thy1.2 promoter. Immunoblotting and immunohistochemistry revealed robust and widespread overexpression of ubiquilin-1 in the brains of the transgenic mice. Similar analysis of R6/2 animals revealed that ubiquilin is localized in huntingtin aggregates and that ubiquilin levels decrease progressively to 30% during the end-stage of disease. We crossed our ubiquilin-1 transgenic line with R6/2 mice to assess whether restoration of ubiquilin levels would delay HD symptoms and pathology. In the double transgenic progeny, ubiquilin levels were fully restored, and this correlated with a 20% increase in lifespan and a reduction in htt inclusions in the hippocampus and cortex. Furthermore, immunoblots indicated that endoplasmic reticulum stress response that is elevated in the hippocampus of R6/2 animals was attenuated by ubiquilin-1 overexpression. However, ubiquilin-1 overexpression neither altered the load of htt aggregates in the striatum nor improved motor impairments in the mice.
Highlights
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and cognitive impairment [1,2]
Because ubiquilin-1 facilitates endoplasmic reticulum associated degradation (ERAD) [21,22] and because htt proteins containing polyglutamine expansions have been implicated in disruption of ERAD [12,14] we investigated whether mice overexpressing ubiquilin-1 had altered endoplasmic reticulum (ER) homeostasis
Our study provides direct in vivo evidence that increasing ubiquilin-1 expression may be beneficial for HD
Summary
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and cognitive impairment [1,2]. Unaffected individuals have between 14 and CAG repeats in this region, while those afflicted with HD have over repeats [4,5] Upon translation, this expansion leads to an aberrantly long tract of polyglutamine (polyQ) residues, which is believed to cause htt protein to misfold and acquire toxic properties [6]. The accumulation of misfolded huntingtin poses a challenge to cellular proteostasis networks, and impairments in the ubiquitin proteasome system [9,10,11], endoplasmic reticulum associated degradation (ERAD) [12,13,14], and autophagy [15,16,17,18] has been reported Efforts to restore these systems are being explored as potential therapy for HD
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