Striatal-Enriched Protein Tyrosine Phosphatase Expression and Activity in Huntington's Disease: A STEP in the Resistance to Excitotoxicity

Abstract

STriatal-Enriched protein tyrosine Phosphatase (STEP) is highly expressed in striatal projection neurons, the neuronal population most affected in Huntington's disease. Here, we examined STEP expression and phosphorylation, which regulates its activity, in N-terminal exon-1 and full-length mutant huntingtin mouse models. R6/1 mice displayed reduced STEP protein levels in the striatum and cortex whereas its phosphorylation was increased in the striatum, cortex and hippocampus. The early increase in striatal STEP phosphorylation levels correlated with a deregulation of the protein kinase A pathway, and decreased calcineurin activity at later stages further contributes to an enhancement of STEP phosphorylation and inactivation. Accordingly, we detected an accumulation of phosphorylated ERK2 and p38, two targets of STEP, in R6/1 mice striatum at advanced stages of the disease. Activation of STEP participates in excitotoxic-induced cell death. Since Huntington's disease mouse models develop resistance to excitotoxicity, we analyzed whether decreased STEP activity was involved in this process. After intrastriatal quinolinic acid (QUIN) injection, we detected higher phosphorylated STEP levels in R6/1 than in wild-type mice suggesting that STEP inactivation could mediate neuroprotection in R6/1 striatum. In agreement, intrastriatal injection of TAT-STEP increased QUIN-induced cell death. R6/2, Tet/HD94 and HdhQ7/Q111 mice striatum also displayed decreased STEP protein and increased phosphorylation levels. In Tet/HD94 mice striatum mutant huntingtin transgene shut-down reestablished STEP expression. In conclusion, the STEP pathway is severely down-regulated in the presence of mutant huntingtin and may participate in compensatory mechanisms activated by striatal neurons that lead to the resistance to excitotoxicity.

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

“…In this way, two parallel pathways converge to regulate STEP phosphorylation and substrate binding: 1) direct phosphorylation of STEP by PKA and 2) indirect regulation of STEP phosphorylation via PKA-induced phosphorylation and activation of DARPP-32, which in turn inhibit PP1 activity. As discussed in more detail in section V, STEP phosphorylation is attenuated in AD (Snyder et al, 2005; and enhanced in HD (Saavedra et al, 2011) and after amphetamine treatment (Valjent et al, 2005).…”

“…On the other hand, too little STEP protein and/or activity can also negatively affect neuronal function and has been recently implicated in Huntington's disease (HD), drug abuse, stroke/ischemia, and inflammatory pain (Valjent et al, 2005;Braithwaite et al, 2008;Tashev et al, 2009;Xu et al, 2009;Saavedra et al, 2011;Yang et al, 2011). Proof-of-concept studies using peptides that manipulate STEP's ability to interact with its substrates, as well as characterization of STEP KO mice, establish that manipulating STEP function may be beneficial for the treatment of these disorders.…”

“…5A) (Xu et al, 2009). Conditions associated with excitotoxicity, such as HD and ischemic neuronal injury, are affiliated with hyperphosphorylation of p38, as well as decreased STEP 61 levels and/or activity (Xu et al, 2009;Saavedra et al, 2011).…”

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

“…In addition, we examined the protein levels of several neuronal markers whose expression is strongly decreased in striatal cells expressing mutant HTT (20)(21)(22)(23)(24)(25) (Figure 4). Treatment with LNA-CTG resulted in a significant recovery of protein levels of the PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), dopamine-and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32), striatal-enriched protein tyrosine phosphatase 46 (STEP46), and postsynaptic density protein 95 (PSD95).…”

A Critical Role for Protein Tyrosine Phosphatase Nonreceptor Type 5 in Determining Individual Susceptibility to Develop Stress-Related Cognitive and Morphological Changes

“…It is a highly conserved member of the PTPN family, with pleiotropic functions in regulating the duration of extracellular signal-regulated kinase (ERK) activation and downstream transcriptional responses after NMDA receptor stimulation (Paul et al, 2003;Valjent et al, 2005), NMDA receptor endocytosis by ␤-amyloid (Snyder et al, 2005), and AMPA receptor endocytosis after metabotropic glutamate receptor stimulation (Zhang et al, 2008), suggesting that PTPN5 signaling may function as a tonic suppressor of synaptic strengthening (Pelkey et al, 2002;Tashev et al, 2009). Recently, it has been observed that PTPN5 is severely downregulated in the presence of mutant huntingtin and may participate in the compensatory mechanisms rendering striatal neurons resistant to excitotoxicity (Saavedra et al, 2011). In addition to its role in regulating synaptic strength, our previous study suggested that PTPN5 activity is permissive for novelty exploration-induced reversal of stress-induced ERK1/2 hyperphosphorylation and alterations of hippocampal long-term synaptic plasticity (Yang et al, 2006).…”