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Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, Tonegawa S. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11489-94. PubMed.
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University of Illinois, Urbana-Champaign
The apparent reversal of some of the phenotypic characteristics of Fragile X syndrome by inhibition of enzymatic activity on a signaling pathway, by Dr. Tonegawa’s group, is very exciting. Of course, not all phenotypes are addressed in this paper, and some behavioral reversal effects appear to be at best partial. That said, this appears to be an elegant demonstration that at least some aspects of the neuromorphological and behavioral phenotypes associated with Fragile X syndrome involve the signaling pathway whereby glutamate triggers ERK phosphorylation leading to protein synthesis. While application of this knowledge at the clinical level remains only a distant possibility, this very clear demonstration that downregulation of a signaling pathway can rescue broad aspects of the Fragile X phenotype indicates that an array of seemingly disparate characteristics may share a common dependence upon the activation of well-known enzymatic signaling systems.
View all comments by I Jeanne WeilerUCLA/VA
Sex and Drugs and Rac and Rho. How Can You Handle a Sick PAK?
Sex-linked mental retardation genes are probably the best understood genetic causes of cognitive deficits. As proximate causes of cognitive dysfunction from birth, they may provide clues to any final common pathways involved in more tangled pathogenic cascades, for example, late-onset dementias. FMRP KO mice are a model for a common genetic cause of autism and mental retardation, Fragile X syndrome, a disease with greater-than-normal cortical spine density and elongated spines. This paper from Hayashi et al. in the Tonegawa laboratory shows that LTP and behavioral deficits (locomotor activity, stereotypy, anxiety, and trace fear conditioning), and spine defects in FMRP KO mice can be ameliorated by crossing in a dominant negative PAK transgene that limits PAK activity by 41 percent in WT mice. They also provide evidence for an interaction between PAK1 and FMRP using Co-IP and a GST PAK1 pull down assay. The authors suggest that PAK inhibitors might be developed as drugs to be used to treat the disorder.
This Tonegawa group paper follows a similarly elegant Neuron paper in which the same scientific team characterized synaptic, LTP, and cognitive deficits in the dnPAK transgenic mice used in this FMRP KO paper. The paper definitively adds FMRP to the list of at least eight X-linked mental retardation genes implicated in Rho GTPase family regulation of actin dynamics in spines (Ramakers, 2002). Since spines are structurally dependent on actin assembly, their formation, motility, maturation, and maintenance require fine regulation of actin assembly and disassembly that is essential for synaptogenesis and synaptic plasticity underlying memory.
The authors have shown that FMRP is a direct PAK1 interacting protein but do not yet know how FMRP fits into the complex signaling network. PAKs are part of a larger family with six PAKs. Group I PAKs ( PAKs 1, 2, and 3) are Rac1/Cdc42 effectors that respond by kinase activation. Group II PAKS (4, 5, and 6) are not activated by Rac1/Cdc42 and are subject to a different system of regulation. (Zhao and Manser, 2004). The Group I PAKS that are direct downstream effectors of Rac1 are embedded in a complex network of Rho GTPase and other targets of extracellular signaling cascades including Ephrins, Plexins, trophic factors, and NMDA receptors.
Loss-of-function missense mutations in PAK3 cause severe mental retardation. Consistent with this, we have previously suggested that PAK defects in AD include focal ectopic hyperactivation but a general loss of cytosolic PAKs and soluble PAK activity (Zhao et al., 2006). This may contribute to spine deficits characterized by the loss of the dendritic spine, actin-binding protein, drebrin. Given the importance of at least PAK3 in normal cognitive function, it might seem counter-intuitive to treat a mental retardation syndrome with a PAK inhibitor. In our subsequent studies, we have found that Aβ oligomers cause an initial rapid aberrant PAK activation and translocation followed by cytosolic deficits in the chronic steady state and in vivo. In the face of PAK dysregulation, we would probably not want to either activate or inhibit to treat AD but restore more balanced regulation.
Too much or too little activity in the network regulating spine actin dynamics and synaptic plasticity can promote cognitive deficits. Thus, AD neuroscientists are very familiar with the essential role of NMDA receptor activation in learning and memory, but also with the excesses of aberrant activation (excitotoxicity) and the successful use of the NMDA modulator memantine to treat AD when pure NMDA inhibitors are toxic. As with γ-secretase, the take-home lesson may be that a modulator aimed at shifting a pathogenic imbalance is likely to be more viable in the clinic.
More generally, defects in these MR/synaptic plasticity pathways can either decrease or increase activity to cause imbalances which result in cognitive deficits. These can occur with excessive LTP or even too many spines as in the case of Fragile X. As Ramakers suggests in his 2002 review: “However, given the tight coupling between many components of the Rho signaling network, any deletion or mutation of crucial components is likely to shift the balance in the network to a suboptimal state, locking actin in a certain configuration (i.e., polymerized or depolymerized, contracted or relaxed). Consequently, neurons might be less responsive to environmental cues, giving rise to suboptimal neuronal connectivity and/or plasticity. In this scenario, it is not important whether a mutation stimulates or inhibits Rho signaling or which Rho GTPase is affected.” The same may be said for ectopic activation or deficits via oligomer-induced Rac/CdC42 activation and downstream PAK pathway effects. However, whether Rac and Rho are druggable remains to be seen.
The fine balance in the Rho signaling network may not be easy to manipulate in a useful way and is certain to involve tight therapeutic windows. The 41 percent inhibition with dnPAK used in the Hayashi et al. study may offer some insight into a window where a dnPAK can inhibit an MR gene and induce cognitive deficits in WT mice and yet is therapeutic in the Fragile X model. This paper, a successful genetic effort to treat one synaptic plasticity defect with another, offers an interesting, albeit perhaps tangential insight into possibilities for AD therapeutics. It’s only Rac and Rho, but I like it.
References:
Ramakers GJ. Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci. 2002 Apr;25(4):191-9. PubMed.
Zhao ZS, Manser E. PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation. Biochem J. 2005 Mar 1;386(Pt 2):201-14. PubMed.
Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci. 2006 Feb;9(2):234-42. PubMed.
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