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PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt

A Saavedra1, J M García-Martínez, X Xifró

  • 1Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143, Barcelona, Spain.

Cell Death and Differentiation
|September 12, 2009
PubMed

Insights

Mutant huntingtin lowers PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) levels, affecting Akt activation in Huntington's disease (HD) models. This downregulation may protect neurons by maintaining Akt activity, even after mutant huntingtin silencing.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) pathophysiology involves gene expression dysregulation.
  • Mutant huntingtin (mHTT) is implicated in HD pathogenesis.
  • PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) dephosphorylates and inactivates Akt at Ser473.

Purpose of the Study:

  • To investigate the regulation of PHLPP1 by mutant huntingtin.
  • To determine the impact of PHLPP1 levels on Akt activation in HD.

Main Methods:

  • Analysis of PHLPP1 protein and mRNA levels in HD mouse models (knock-in and transgenic) and HD patient samples.
  • Quantitative PCR to assess PHLPP1 mRNA expression.
  • Western blot analysis to measure phosphorylated Akt (Ser473) levels.
  • Investigation using a conditional Tet/HD94 mouse model to observe PHLPP1 and Akt levels after mHTT shutdown.

Main Results:

  • Decreased PHLPP1 protein and mRNA levels were observed in the striatum of various HD models and in HD patient putamen.
  • Increased phosphorylated Akt (Ser473) levels were detected in the striatum of HD models.
  • In the Tet/HD94 model, PHLPP1 levels recovered to wild-type levels after mHTT shutdown, while phospho-Akt levels partially decreased.

Conclusions:

  • Mutant huntingtin downregulates PHLPP1 expression.
  • Reduced PHLPP1 in the striatum contributes to sustained Akt activation in HD.
  • Sustained Akt activation may offer neuroprotection and promote neuronal recovery after mHTT silencing.

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