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A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity.

Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B - Elife (2015)

Bottom Line: Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum.Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models.Thus, our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.

ABSTRACT
Huntington's disease (HD) represents an important model for neurodegenerative disorders and proteinopathies. It is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. Gpr52 modulates Htt via cAMP-dependent but PKA independent mechanisms. Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum. Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models. Thus, our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.

No MeSH data available.


Related in: MedlinePlus

Over-expression of human Gpr52 cDNA in STHdh cells.Representative western-blots showing increased Htt levels and over-expression of human Gpr52 (hGpr52) in STHdhQ7/Q111 transfected with the hGpr52 cDNA.DOI:http://dx.doi.org/10.7554/eLife.05449.007
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fig3s1: Over-expression of human Gpr52 cDNA in STHdh cells.Representative western-blots showing increased Htt levels and over-expression of human Gpr52 (hGpr52) in STHdhQ7/Q111 transfected with the hGpr52 cDNA.DOI:http://dx.doi.org/10.7554/eLife.05449.007

Mentions: Gpr52 is enriched in the striatum (Sawzdargo et al., 1999; Komatsu et al., 2014), and thus may contribute to the selective stabilization of Htt there (Tsvetkov et al., 2013). Consistent with this, over-expression of Gpr52 cDNA (Figure 3—figure supplement 1) or treatment with an agonist reserpine (Komatsu et al., 2014) (Figure 3A) leads to a dose-dependent increase of Htt (Figure 3B–C), confirming Gpr52 as an Htt stabilizer.10.7554/eLife.05449.006Figure 3.Gpr52 modulates Htt levels via cAMP dependent but PKA independent pathways.


A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity.

Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B - Elife (2015)

Over-expression of human Gpr52 cDNA in STHdh cells.Representative western-blots showing increased Htt levels and over-expression of human Gpr52 (hGpr52) in STHdhQ7/Q111 transfected with the hGpr52 cDNA.DOI:http://dx.doi.org/10.7554/eLife.05449.007
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4372774&req=5

fig3s1: Over-expression of human Gpr52 cDNA in STHdh cells.Representative western-blots showing increased Htt levels and over-expression of human Gpr52 (hGpr52) in STHdhQ7/Q111 transfected with the hGpr52 cDNA.DOI:http://dx.doi.org/10.7554/eLife.05449.007
Mentions: Gpr52 is enriched in the striatum (Sawzdargo et al., 1999; Komatsu et al., 2014), and thus may contribute to the selective stabilization of Htt there (Tsvetkov et al., 2013). Consistent with this, over-expression of Gpr52 cDNA (Figure 3—figure supplement 1) or treatment with an agonist reserpine (Komatsu et al., 2014) (Figure 3A) leads to a dose-dependent increase of Htt (Figure 3B–C), confirming Gpr52 as an Htt stabilizer.10.7554/eLife.05449.006Figure 3.Gpr52 modulates Htt levels via cAMP dependent but PKA independent pathways.

Bottom Line: Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum.Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models.Thus, our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.

ABSTRACT
Huntington's disease (HD) represents an important model for neurodegenerative disorders and proteinopathies. It is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. Gpr52 modulates Htt via cAMP-dependent but PKA independent mechanisms. Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum. Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models. Thus, our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.

No MeSH data available.


Related in: MedlinePlus