PIP4Kγ as a potential target for Huntington's disease

Journal Article · Wed Oct 03 00:00:00 EDT 2018 · FASEB Journal

DOI:https://doi.org/10.1096/fasebj.31.1_supplement.946.8· OSTI ID:1787051

Giridharan, Sai Srinivas Panapakkam ^[1]; Al‐Ramahi, Ismael ^[2]; Hasegawa, Junya ^[1]; Safren, Nathanial ^[3]; Patnaik, Samarjit ^[4]; Gee, Amanda ^[4]; Titus, Steve ^[4]; Zheng, Wei ^[4]; Ferrer, Marc ^[4]; Southall, Noel ^[4]; Barmada, Sami ^[3]; Botas, Juan ^[2]; Marugan, Juan ^[4]; Weisman, Lois S. ^[5]

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1. Life Sciences Institute, University of Michigan Ann Arbor MI
2. Department of Molecular and Human Genetics Baylor College of Medicine Houston TX
3. Department of Neurology University of Michigan Ann Arbor MI
4. Division of Pre‐Clinical Innovation, National Center for Advancing Translational Sciences NIH Bethesda MD
5. Cell and Developmental Biology University of Michigan Ann Arbor MI, Life Sciences Institute, University of Michigan Ann Arbor MI

Phosphoinositide lipids provide spatial and temporal regulation of cell signaling and membrane traffic. The PI5P‐4‐kinase family is one of the less studied phosphoinositide lipid kinases. These enzymes catalyze the conversion of phosphatidylinositol 5‐phosphate to phosphatidylinositol 4,5‐bis phosphate. A recent study by Vicinanza et al., a suggested that depletion of the PI5P‐4‐kinase, PIP4Kγ promotes a non‐canonical autophagy pathway. Moreover, this depletion reduced the presence of huntingtin‐exon1‐polyglutamine aggregates. Expression of exon1 of huntingtin with an extended polyglutamine tract is a model for huntingtin protein aggregates. To further test the hypothesis that PIP4Kγ is a potential target to reduce huntingtin aggregates, we tested the depletion of PIP4Kγ in cell culture models that express full length mutant huntingtin (mHtt). We determined that depletion of PIP4Kγ, but not PIP4Kα or PIP4Kβ, lowers the levels of mHtt in patient fibroblasts and in immortalized Hdh ^Q111 mouse striatal neurons. We show that PIP4Kγ‐dependent depletion of mHtt requires lysosomal function because the depletion is blocked by the lysosomal inhibitor, bafilomycin A1. Moreover, we show that depletion of PIP4Kγ increases autophagic flux, as measured by an increase in LC3‐II levels by western blot analysis and an increase in LC3‐II puncta by microscopy. Our studies suggest that PIP4kγ should be further pursued as a target for Huntington's disease.

Support or Funding Information

This work was supported by AHA postdoctoral fellowship 14POST20480137 (Sai Srinivas Panapakkam Giridharan), NIH grants R01GM050403 and NS064015 (Lois S Weisman) and by HSS funding 1R03MH084839 (Juan Marugan)

• Sponsoring Organization: USDOE
• OSTI ID: 1787051
• Journal Information: FASEB Journal, Journal Name: FASEB Journal Journal Issue: S1 Vol. 31; ISSN 0892-6638
• Publisher: FASEB
• Country of Publication: United States
• Language: English