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Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.

Lessing D, Bonini NM - PLoS Biol. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Pennsylvania, Howard Hughes Medical Institute, Philadelphia, Pennsylvania, United States of America.

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.

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Related in: MedlinePlus

The PAM2 Motif of Atx2 Is Required for Enhancement of Atx3 Degeneration and for Atx2 Toxicity(A and B) External eye and internal retinal sections. Retinal thickness is indicated by double-headed yellow arrows. (A) Expression of Atx2 lacking the PAM2 motif (Atx2ΔP) causes a disrupted eye with (top) external roughness and dorsal discoloration and (below) disorganized internal structure. Genotype: Gmr-Gal4/+; UAS-Atx2ΔP/+. (B) Co-expression of Atx2ΔP with SCA3trQ78 does not enhance SCA3trQ78 degeneration; the eye looks identical to that of flies expressing Atx2ΔP only. Genotype: Gmr-Gal4/+; UAS-SCA3trQ78(w)/UAS-Atx2ΔP.(C and D) Pseudopupil preparations to highlight internal retinal degeneration. (C) Flies expressing Atx2ΔP maintain a normal retina over time, with a mean of seven PR (18 d shown, genotype: Rh1-Gal4/UAS-Atx2ΔP). (D) Coexpression of Atx2ΔP with SCA3trQ78 has minimal effect on SCA3trQ78 degeneration, with a mean of 6.7 PR (6 d, UAS-SCA3trQ78(s)/+; Rh1-Gal4/UAS-Atx2ΔP); normally SCA3trQ78 expression by itself results in a mean of 6.9 PR at 6 d (see Figure 2A).
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pbio-0060029-g005: The PAM2 Motif of Atx2 Is Required for Enhancement of Atx3 Degeneration and for Atx2 Toxicity(A and B) External eye and internal retinal sections. Retinal thickness is indicated by double-headed yellow arrows. (A) Expression of Atx2 lacking the PAM2 motif (Atx2ΔP) causes a disrupted eye with (top) external roughness and dorsal discoloration and (below) disorganized internal structure. Genotype: Gmr-Gal4/+; UAS-Atx2ΔP/+. (B) Co-expression of Atx2ΔP with SCA3trQ78 does not enhance SCA3trQ78 degeneration; the eye looks identical to that of flies expressing Atx2ΔP only. Genotype: Gmr-Gal4/+; UAS-SCA3trQ78(w)/UAS-Atx2ΔP.(C and D) Pseudopupil preparations to highlight internal retinal degeneration. (C) Flies expressing Atx2ΔP maintain a normal retina over time, with a mean of seven PR (18 d shown, genotype: Rh1-Gal4/UAS-Atx2ΔP). (D) Coexpression of Atx2ΔP with SCA3trQ78 has minimal effect on SCA3trQ78 degeneration, with a mean of 6.7 PR (6 d, UAS-SCA3trQ78(s)/+; Rh1-Gal4/UAS-Atx2ΔP); normally SCA3trQ78 expression by itself results in a mean of 6.9 PR at 6 d (see Figure 2A).

Mentions: To provide insight into the mechanism by which Atx2 modulates polyQ toxicity, we determined whether the conserved 12-amino acid PAM2 motif of the Atx2 protein was required for enhancement of SCA3 toxicity. The PAM2 motif is required for Atx2 to associate with PABP, and together with the RNA-binding Lsm domain, it mediates the colocalization of Atx2 with PABP in polyribosomes [16]. We tested whether a construct lacking the conserved PAM2 domain, UAS-Atx2ΔP [16], could modulate Atx3 toxicity. Atx2ΔP retains partial Atx2 function, since it delays embryonic lethality caused by complete loss of atx2 function [16]. The Atx2ΔP transgenic line expressed the protein at a level comparable to that of the strongly expressing Atx2(s) line (Figure S5). Expression of Atx2ΔP driven by Gmr-Gal4 caused a disrupted eye phenotype distinct from that caused by up-regulation of normal Atx2: black patches were present on the surface, and the underlying retina was disorganized although intact, showing no evidence of degeneration (Figure 5A). In striking contrast to normal Atx2 protein, coexpression of Atx2ΔP failed to enhance SCA3trQ78 toxicity: the flies showed an eye phenotype identical to that caused by Atx2ΔP alone (Figure 5B; compare to Figure 1D).


Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila.

Lessing D, Bonini NM - PLoS Biol. (2008)

The PAM2 Motif of Atx2 Is Required for Enhancement of Atx3 Degeneration and for Atx2 Toxicity(A and B) External eye and internal retinal sections. Retinal thickness is indicated by double-headed yellow arrows. (A) Expression of Atx2 lacking the PAM2 motif (Atx2ΔP) causes a disrupted eye with (top) external roughness and dorsal discoloration and (below) disorganized internal structure. Genotype: Gmr-Gal4/+; UAS-Atx2ΔP/+. (B) Co-expression of Atx2ΔP with SCA3trQ78 does not enhance SCA3trQ78 degeneration; the eye looks identical to that of flies expressing Atx2ΔP only. Genotype: Gmr-Gal4/+; UAS-SCA3trQ78(w)/UAS-Atx2ΔP.(C and D) Pseudopupil preparations to highlight internal retinal degeneration. (C) Flies expressing Atx2ΔP maintain a normal retina over time, with a mean of seven PR (18 d shown, genotype: Rh1-Gal4/UAS-Atx2ΔP). (D) Coexpression of Atx2ΔP with SCA3trQ78 has minimal effect on SCA3trQ78 degeneration, with a mean of 6.7 PR (6 d, UAS-SCA3trQ78(s)/+; Rh1-Gal4/UAS-Atx2ΔP); normally SCA3trQ78 expression by itself results in a mean of 6.9 PR at 6 d (see Figure 2A).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2235903&req=5

pbio-0060029-g005: The PAM2 Motif of Atx2 Is Required for Enhancement of Atx3 Degeneration and for Atx2 Toxicity(A and B) External eye and internal retinal sections. Retinal thickness is indicated by double-headed yellow arrows. (A) Expression of Atx2 lacking the PAM2 motif (Atx2ΔP) causes a disrupted eye with (top) external roughness and dorsal discoloration and (below) disorganized internal structure. Genotype: Gmr-Gal4/+; UAS-Atx2ΔP/+. (B) Co-expression of Atx2ΔP with SCA3trQ78 does not enhance SCA3trQ78 degeneration; the eye looks identical to that of flies expressing Atx2ΔP only. Genotype: Gmr-Gal4/+; UAS-SCA3trQ78(w)/UAS-Atx2ΔP.(C and D) Pseudopupil preparations to highlight internal retinal degeneration. (C) Flies expressing Atx2ΔP maintain a normal retina over time, with a mean of seven PR (18 d shown, genotype: Rh1-Gal4/UAS-Atx2ΔP). (D) Coexpression of Atx2ΔP with SCA3trQ78 has minimal effect on SCA3trQ78 degeneration, with a mean of 6.7 PR (6 d, UAS-SCA3trQ78(s)/+; Rh1-Gal4/UAS-Atx2ΔP); normally SCA3trQ78 expression by itself results in a mean of 6.9 PR at 6 d (see Figure 2A).
Mentions: To provide insight into the mechanism by which Atx2 modulates polyQ toxicity, we determined whether the conserved 12-amino acid PAM2 motif of the Atx2 protein was required for enhancement of SCA3 toxicity. The PAM2 motif is required for Atx2 to associate with PABP, and together with the RNA-binding Lsm domain, it mediates the colocalization of Atx2 with PABP in polyribosomes [16]. We tested whether a construct lacking the conserved PAM2 domain, UAS-Atx2ΔP [16], could modulate Atx3 toxicity. Atx2ΔP retains partial Atx2 function, since it delays embryonic lethality caused by complete loss of atx2 function [16]. The Atx2ΔP transgenic line expressed the protein at a level comparable to that of the strongly expressing Atx2(s) line (Figure S5). Expression of Atx2ΔP driven by Gmr-Gal4 caused a disrupted eye phenotype distinct from that caused by up-regulation of normal Atx2: black patches were present on the surface, and the underlying retina was disorganized although intact, showing no evidence of degeneration (Figure 5A). In striking contrast to normal Atx2 protein, coexpression of Atx2ΔP failed to enhance SCA3trQ78 toxicity: the flies showed an eye phenotype identical to that caused by Atx2ΔP alone (Figure 5B; compare to Figure 1D).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Pennsylvania, Howard Hughes Medical Institute, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH
Related in: MedlinePlus