Taking STEPs forward to understand fragile X syndrome.
Susan M Goebel-Goody1, Paul J Lombroso
1Yale University School of Medicine, New Haven, CT 06520, USA. susan.goebel-goody@yale.edu
Dysregulated STriatal-Enriched protein tyrosine Phosphatase (STEP) may contribute to fragile X syndrome (FXS) pathophysiology. Targeting STEP offers a potential therapeutic strategy for FXS and related neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Fragile X syndrome (FXS) research prioritizes understanding molecular mechanisms of deficits.
- Exaggerated metabotropic glutamate receptor (mGluR) long-term depression (LTD) in FXS mice suggests a role for synaptic plasticity regulators.
Purpose of the Study:
- To investigate the potential role of STriatal-Enriched protein tyrosine Phosphatase (STEP) in FXS pathophysiology.
- To review regulatory mechanisms of STEP and its implications in FXS and other neurological disorders.
Main Methods:
- Literature review focusing on STEP's function in synaptic plasticity.
- Analysis of STEP's regulation by protein synthesis, ubiquitination, proteolysis, and phosphorylation.
- Discussion of STEP's implications in FXS and Alzheimer's disease.
Main Results:
- STEP is identified as an "LTD protein" mediating AMPA receptor internalization during mGluR LTD.
- STEP promotes NMDA receptor endocytosis and inactivates ERK1/2 and Fyn, opposing synaptic strengthening.
- Dysregulation of STEP is hypothesized to contribute to FXS pathophysiology.
Conclusions:
- STEP's dysregulation is a potential contributor to FXS.
- Pharmacological targeting of STEP may offer a promising therapeutic avenue for FXS.
- STEP's role extends to other neurological conditions, including Alzheimer's disease.
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