Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

富亮氨酸重复激酶2抑制剂作为新型帕金森病治疗剂的研究进展

帕金森病(PD)是以多巴胺能神经系统退行性病变为特征的多因素疾病。对其进行分型研究,发展针对PD发病机制的治疗药物是提高PD治疗效果的必由之路。富亮氨酸重复激酶2(LRRK2)基因突变是部分家族遗传性PD和散发性PD的直接原因。LRRK2基因突变会导致LRRK2活性增加,进而导致神经退行性病变。因此,发展LRRK2抑制剂调控LRRK2活性有望成为新的PD治疗方法。LRRK2既是激酶,也是小GTP酶,存在2个药物作用位点,因此,目前LRRK2抑制剂有2类,一类是LRRK2激酶位点抑制剂,另一类是LRRK2 GTP结合位点抑制剂。本文综述了LRRK2及其抑制剂的研究进展。

LRRK2G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson's Disease

The G2019S mutation of the leucine-rich repeat kinase 2(LRRK2)is the most common genetic cause of Parkinson's disease (PD).However,the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated.We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein.The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A.It was found that α-synuclein was mainly degraded in lysosomes.LRRK2G2019S inhibited the degradation of α-synuclein,and promoted its aggregation.LRRK2G 2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L.Furthermore,the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity.These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.

Chemical control of receptor kinase signaling by rapamycin-induced dimerization

Membrane-localized leucine-rich repeat receptor kinases(LRR-RKs)sense diverse extracellular signals,and coordinate and specify cellular functions in plants.However,functional understanding and identification of the cellular signaling of most LRR-RKs remain a major challenge owing to their genetic redundancy,the lack of ligand information,and subtle phenotypes of LRR-RK overexpression.Here,we report an engineered rapamycin-inducible dimerization(RiD)receptor system that triggers a receptor-specific LRR-RK signaling independent of their cognate ligands or endogenous receptors.Using the RiD-receptors,we demonstrated that the rapamycin-mediated association of chimeric cytosolic kinase domains from the BRI1/BAK1 receptor/co-receptor,but not the BRI1/BRI1 or BAK1/BAK1 homodimer,is sufficient to activate downstream brassinosteroid signaling and physiological responses.Furthermore,we showed that the engineered RiD-FLS2/BAK1 could activate flagellin-22-mediated immune signaling and responses.Using the RiD system,we also identified the potential function of an unkmown orphan receptor in immune signaling and revealed the differential activities of SERK co-receptors of LRR-RKs.Our results indicate that the RiD method can serve as a synthetic biology tool for precise temporal manipulation of LRR-RK signaling and for understanding LRR-RK biology.

LRRK2激酶在帕金森病中的致病机制及相关抑制剂的研发进展

目前帕金森病(PD)治疗的主要方法是以改善运动症状为核心的多巴胺替代治疗,但潜在的疾病进程难以被打断或者延缓。随着PD遗传研究的跨越式发展,一系列单基因突变和患病风险位点被陆续发现,疾病发生发展的分子机制得以进一步阐明,也为PD患者个体化治疗奠定了理论基础。PD相关基因LRRK2作为潜在治疗靶点,受到广泛关注。文中旨在对LRRK2基因的结构功能、致病机制、最新治疗研究进展进行综述。