Abstract
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.
Highlights
The polyglutamine diseases are caused by the expansion of a CAG repeat encoding glutamine within the open reading frames of at least nine genes [1]
Six forms of spinal cerebellar ataxia (SCA1, À2, À3, À6, À7, and À17) 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
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
Summary
The polyglutamine diseases are caused by the expansion of a CAG repeat encoding glutamine within the open reading frames of at least nine genes [1]. The disease state is thought to be due to a misfolded conformation of the pathogenic protein (termed an Ataxin in most forms of spinal cerebellar ataxia [SCAs]), which accumulates intracellularly in ubiquitinated inclusions along with chaperones and subunits of the proteasome [2]. The severity of facial muscle twitch in patients with SCA3 is correlated with the length of the CAG repeat in the normal alleles of the SCA2 gene ATXN2 [5]. Both SCA2 and SCA3 are unusual among the dominantly inherited ataxias in that they can manifest with parkinsonism [6]. The normal Ataxin-2 (Atx2) protein can be detected in the pathogenic inclusions of SCA3 patients, and, likewise, normal Atx protein localizes to the inclusions formed in SCA2 patients [7]
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