Alpha-Crystallin Promotes Rat Axonal Regeneration Through Regulation of RhoA/Rock/Cofilin/MLC Signaling Pathways

Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Journal of Molecular Neuroscience (Impact Factor: 2.34). 05/2011; 46(1):138-44. DOI: 10.1007/s12031-011-9537-z
Source: PubMed


Intravitreal injection of α-crystallin can promote axons from optic nerve regeneration after crushing in rats. We have previously demonstrated that α-crystallin can counteract the effect of myelin inhibitory factors and stimulate neurite growth. And a common crucial signaling event for myelin inhibitory factors is the activation of RhoA. To investigate whether α-crystallin counteracts the inhibitory effect of myelin inhibitory factors through regulation of RhoA/Rock signaling pathway, α-crystallin (10(-4) g/L) was injected into rat vitreous at the time the optic nerve crushed. The RhoA protein activity and the expression of RhoA and Rock were evaluated after 3 days of optic nerve axotomy. Rock downstream effectors, phosphorylated cofilin, and phosphorylated myosin light chain were detected when retinal neurons were cultured for 3 days. Axonal regeneration and neurites growth of cultured cells were observed also. Our results showed that α-crystallin decreased the RhoA protein activity and the phosphorylation of both cofilin and myosin light chain, and promoted the axonal growth. However, the expression of RhoA and Rock was not affected by α-crystallin. These findings indicated that α-crystallin could counteract the effect of myelin inhibitory factors through the regulation of RhoA/Rock signaling pathway.

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    • "Interestingly, application of α-crystallin to the vitreous resulted in a decreased RhoA and ROCK activity, and a reduction of p-cofilin and p-MLC, which was associated with increased axonal regeneration in vivo. Thus, pro-regenerative effects of crystallins may, at least partially, be attributed to the regulation of the RhoA/ROCK/cofilin pathway (Wang et al., 2011). Because α-crystallin interacts with α6-integrin membrane receptor complexes and alters their cellular signaling (Menko and Andley, 2010) a speculative link to RhoA consists in the prevention of the GDP to GTP exchange of RhoA through integrin membrane complex binding of guanine nucleotide exchange factors (Wettschureck and Offermanns, 2002). "
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    ABSTRACT: Regenerative failure in the CNS largely depends on pronounced growth inhibitory signaling and reduced cellular survival after a lesion stimulus. One key mediator of growth inhibitory signaling is Rho-associated kinase (ROCK), which has been shown to modulate growth cone stability by regulation of actin dynamics. Recently, there is accumulating evidence the ROCK also plays a deleterious role for cellular survival. In this manuscript we illustrate that ROCK is involved in a variety of intracellular signaling pathways that comprise far more than those involved in neurite growth inhibition alone. Although ROCK function is currently studied in many different disease contexts, our review focuses on neurorestorative approaches in the CNS, especially in models of neurotrauma. Promising strategies to target ROCK by pharmacological small molecule inhibitors and RNAi approaches are evaluated for their outcome on regenerative growth and cellular protection both in preclinical and in clinical studies.
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