Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice

Abstract

Among the eight progressive neurodegenerative diseases caused by polyglutamine expansions, spinocerebellar ataxia type 7 (SCA7) is the only one to display degeneration in both brain and retina. We show here that mice overexpressing full-length mutant ataxin-7[Q90] either in Purkinje cells or in rod photoreceptors have deficiencies in motor coordination and vision, respectively. In both models, although with different time courses, an N-terminal fragment of mutant ataxin-7 accumulates into ubiquitinated nuclear inclusions that recruit a distinct set of chaperone/proteasome subunits. A severe degeneration is caused by overexpression of ataxin-7[Q90] in rods, whereas a similar overexpression of normal ataxin-7[Q10] has no obvious effect. The degenerative process is not limited to photoreceptors, showing secondary alterations of post-synaptic neurons. These findings suggest that proteolytic cleavage of mutant ataxin-7 and trans-neuronal responses are implicated in the pathogenesis of SCA7.

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

“…Heterozygous R7E transgenic mice maintained in a C57BL/6 background (Yvert et al, 2000) were crossed with homozygous or heterozygous JunAA knock-in mice of mixed 129xC57BL/6xCBA background (kindly provided by E.F. Wagner). In JunAA mice, serine 63 and 73 of c-Jun are mutated to alanines.…”

“…In JunAA mice, serine 63 and 73 of c-Jun are mutated to alanines. For genotyping, mouse tail DNA was screened by PCR as described (Behrens et al, 1999;Yvert et al, 2000). The matings were designed to generate litters for different groups to be compared (i.e.…”

“…Mutations in phototransduction genes and their transcriptional regulators are associated with photoreceptor degeneration, thus allowing direct correlations between gene mutation and cell function (Molday, 1998;Rattner et al, 1999;Pacione et al, 2003). To decipher the molecular basis of polyQ toxicity, we developed a SCA7 transgenic mouse model -R7E -to specifically target rod photoreceptors using the rhodopsin promoter (Yvert et al, 2000). This mouse model reproduced the primary features of SCA7 pathology, including progressive functional alteration, followed by rod degeneration.…”

Modèles animaux des maladies neuro-dégénératives

“…Ces SCA (spinocerebellar ataxia) autosomiques dominantes s'accompagnent presque invariablement d'inclusions nucléaires lorsqu'elles sont en rapport avec l'allongement d'un segment répétitif CAG. Plusieurs souris transgéniques SCA ont été produites, notamment la souris SCA7 chez laquelle l'ataxie est associée, comme chez l'homme, à une rétinite pigmentaire et à des inclusions nucléaires [41]. Le rôle physiopathologique des inclusions nucléaires CAG, étudié en détail chez les souris transgéniques et en culture cellulaire, reste discuté : protecteur, par séquestration d'une protéine toxique [42], ou délétère, en piégeant dans le noyau des facteurs de transcription (pour revue, voir [43]).…”

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

“…Disease genes share no sequence homology except for the poly-Q coding sequences, indicating a critical role of the glutamine expansion in pathogenesis (Igarashi et al, 1998). In addition to DRPLA, expression of poly-Q expanded mutant proteins identified in HD, SCA1, SCA3, or SCA7 also induced neurodegeneration in mice (Mangiarini et al, 1996;Clark et al, 1997;Davies et al, 1997;Yvert et al, 2000;Cemal et al, 2002;Benn et al, 2005). Dominant inheritance of these diseases is consistent with a neomorphic feature of the poly-Q expansion.…”