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.
    Frontiers in Molecular Neuroscience 11/2011; 4(39):39. DOI:10.3389/fnmol.2011.00039 · 4.08 Impact Factor
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    ABSTRACT: Transplantation of cultured olfactory ensheathing cells (OECs) into lesions can promote axonal regeneration. However, the acutely injured CNS environment affects the survival and proliferation of OECs which might impair its therapy effects. To investigate whether α-crystallin can promote the survival and proliferation of OECs, OECs were cultured with α-crystallin. The survival of OECs was assessed by counting the numbers of p75-labeled OECs. Cellular proliferative activity was estimated by flow cytometry and quantification of BrdU-labeled cells. Phosphorylated p85, Akt and mammalian target of rapamycin (mTOR) were detected when OECs were culture for 7 days. Our results showed that the numbers of p75-labeled or Brdu-labeled OECs in α-crystallin group were much more than that in control group. And α-crystallin increased the phosphorylation of both p85, Akt and mTOR. LY294002 abrogated the ability of α-crystallin to phosphorylate Akt and mTOR, and decreased the percentage of cells in S and G2/M stage which were treated with α-crystallin. These findings indicated that α-crystallin positively regulated the activation of PI3K/Akt/mTOR signaling pathway and promote the proliferation and survival of cultured OECs.
    Neuroscience Letters 11/2012; 531(2). DOI:10.1016/j.neulet.2012.10.057 · 2.03 Impact Factor
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    ABSTRACT: Optic nerve injury is a consequence of numerous ophthalmic conditions including glaucoma, a leading cause of global blindness. In adult humans, the optic nerve displays limited regenerative capacity, typical of neurons of the CNS. In efforts to address this issue, a number of recent advances have been made in the identification of potential therapeutic targets that directly inhibit or stimulate optic nerve regeneration, with more work implicating several other factors. These factors can be categorized as being intracellular or extracellular with respect to the neuron, or inflammatory cell-derived. In addition to these therapeutic strategies, it is important to guide the regrowing axons to their correct destination. Recent work has identified several developmental guidance factors important in regeneration, and potential therapeutic targets for the future. This review discusses newly identified and existing regeneration factors and evaluates current cellular- and nanotechnology-based therapies that aim to aid and guide optic nerve regeneration to achieve functional recovery.
    Expert Review of Ophthalmology 12/2012; 7(6):533-554. DOI:10.1586/eop.12.66
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