Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.
Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.
复制标题
聚谷氨酰胺基因相互作用以调节果蝇中神经退行性的严重程度和进展。
DOI：
10.1371/journal.pbio.0060029
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发表时间：
2008-02
期刊：
影响因子：
9.8
通讯作者：
Bonini, Nancy M.
中科院分区：
文献类型：
--
作者：
Lessing, Derek;Bonini, Nancy M.
The expansion of polyglutamine tracts in a variety of proteins causes devastating, dominantly inherited neurodegenerative diseases, including six forms of spinal cerebellar ataxia (SCA). Although a polyglutamine expansion encoded in a single allele of each of the responsible genes is sufficient for the onset of each disease, clinical observations suggest that interactions between these genes may affect disease progression. In a screen for modifiers of neurodegeneration due to SCA3 in Drosophila, we isolated atx2, the fly ortholog of the human gene that causes a related ataxia, SCA2. We show that the normal activity of Ataxin-2 (Atx2) is critical for SCA3 degeneration and that Atx2 activity hastens the onset of nuclear inclusions associated with SCA3. These activities depend on a conserved protein interaction domain of Atx2, the PAM2 motif, which mediates binding of cytoplasmic poly(A)-binding protein (PABP). We show here that PABP also influences SCA3-associated neurodegeneration. These studies indicate that the toxicity of one polyglutamine disease protein can be dramatically modulated by the normal activity of another. We propose that functional links between these genes are critical to disease severity and progression, such that therapeutics for one disease may be applicable to others. Six forms of spinal cerebellar ataxia (SCA1, −2, −3, −6, −7, and −17) are caused by dominant mutations in the respective genes. Patients suffering from these different forms of SCA have similar symptoms of progressive adult-onset neurodegeneration, and the same causative mutation, a CAG repeat expansion encoding an expanded run of polyglutamine. Although the affected proteins are distinct and share no sequence similarity beyond the polyglutamine domains, clinical and other observations hint at interactions between the genes that cause different forms of SCA. Using Drosophila as a model for human disease, we now detail an interaction between the genes associated with SCA3 and SCA2. We find that toxicity and neurodegeneration induced by pathogenic forms of SCA3 depend on the normal activity of the fly counterpart of the gene associated with SCA2, ataxin-2. This interaction depends on a conserved protein-interaction motif of Ataxin-2, and a protein that binds this motif, cytoplasmic poly(A)-binding protein (PABP), also modulates SCA3 degeneration. These results suggest that the normal roles of Ataxin-2 and PABP, potentially to regulate the translation of select target mRNAs, are critical to SCA3 disease. These studies also highlight how a fly model can serve to enhance and extend intriguing clinical findings of the human disease. In a fly model of spinal cerebellar ataxia type 3 (SCA3), toxicity of the pathogenic human protein is shown to depend on the normal activity of the fly ortholog of a gene that causes the related human disease, SCA2.
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