Ataxin-1 Nuclear Localization and Aggregation

Abstract

Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1[82] with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1[77] containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.

Mutant huntingtin impairs Ku70-mediated DNA repair

“…This is consistent with our previous result, showing that a reduction of HMGBs essential for architectural DNA alteration (Thomas and Travers, 2001) leads to genotoxic stress . It is also in line with previous findings that nuclear events largely initiate polyQ pathologies (Klement et al, 1998;Saudou et al, 1998;Katsuno et al, 2003).…”

“…Hoshino et al, 2006). The genotoxic stress hypothesis seems consistent with previous notions that nuclear events initiate the polyQ disease pathology (Klement et al, 1998;Saudou et al, 1998;Katsuno et al, 2003). Moreover, regarding cell death, activation of p53-p73 pathway leads to apoptosis in cultured cells (Bae et al, 2005) and to nonapoptotic, atypical cell death in primary neurons (Hoshino et al, 2006).…”

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

“…13 To investigate the potential protective effect of rAAV1.miS1 on this phenotype, brain sections were evaluated by anti-calbindin staining of sagittal sections, and ML widths quantified. In control treated B05 animals, lobules III-IV/V have marked thinning, as do sections from animals injected with 8×10 8 vg of rAAV1.miS1 compared to wildtype littermates (Fig 3A).…”

"In vivo" toxicity of a truncated version of the Drosophila Rst-IrreC protein is dependent on the presence of a glutamine-rich region in its intracellular domain

“…This raises the question of whether the pCa18Z toxic effect has the same pathogenic causes of the aforementioned diseases, or it is a consequence of a completely different mechanism. A characteristic pathological feature, present in all glutamine repeat diseases reported so far is the aggregation, in the nucleus, of the expanded polyglutamine tracts present in the mutant proteins which became enclosed by a single amorphous intranuclear inclusion, although this seems to be a protection mechanism rather than a trigger for the apoptotic neuronal degeneration responsible for the onset of the disease (Klement et al 1998, Saudou et al 1998. Their presence in larvae of embryos injected with pCa18Z would strongly argue for a common pathogenic mechanism between glutamine repeat disease and the post embryonic lethality associated to pCa18Z described here.…”