Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Hensley, Kenneth; Christov, Alexandar; Kamat, Siddhesh S.; Zhang, X. C.; Jackson, Kenneth W.; Snow, S.; Post, Jan Andries

doi:10.1523/jneurosci.5247-09.2010

Cited by 75 publications

(126 citation statements)

References 44 publications

(83 reference statements)

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“…CRMP2 itself has no known enzymatic activity but interacts with its binding partners to affect microtubule dynamics, neurite outgrowth and retraction, neural differentiation, dendrite/ axon fate specification, kinesin-dependent axonal transport, Ca 2+ homeostasis, neurotransmitter release, and other essential neurophysiology still being elucidated [1][2][3][4][5][6][7][8][9][10][11][12][13]. Because the acronym CRMP2 best describes the predominant phenotypic behavior of the protein with which this review concerns itself, i.e., neurite length modulation, and the formal DPYSL2 nomenclature specifies no enzymological relationship of CRMP2 to DPYS, this review will refer to the protein as CRMP2 with the exception of…”

Section: Structure Expression Pattern and Protein Interactome Of Dpmentioning

confidence: 99%

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

et al. 2011

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Collapsin response mediator protein-2 (DPYSL2 or CRMP2) is a multifunctional adaptor protein within the central nervous system. In the developing brain or cell cultures, CRMP2 performs structural and regulatory functions related to cytoskeletal dynamics, vesicle trafficking and synaptic physiology whereas CRMP2 functions in adult brain are still being elucidated. CRMP2 has been associated with several neuropathologic or psychiatric conditions including Alzheimer's disease (AD) and schizophrenia, either at the level of genetic polymorphisms; protein expression; post-translational modifications; or protein/protein interactions. In AD, CRMP2 is phosphorylated by glycogen synthase kinase-3β (GSK3β) and cyclin dependent protein kinase-5 (CDK5), the same kinases that act on tau protein in generating neurofibrillary tangles (NFTs). Phosphorylated CRMP2 collects in NFTs in association with the synaptic structure-regulating SRA1/WAVE1 (specifically Rac1-associated protein-1/WASP family verprolin-homologous protein-1) complex. This phenomenon could plausibly contribute to deficits in neural and synaptic structure that have been well documented in AD. This review discusses the essential biology of CRMP2 in the context of nascent data implicating CRMP2 perturbations as either a correlate of, or plausible contributor to, diverse neuropathologies. A discussion is made of recent findings that the atypical antidepressant tianeptine increases CRMP2 expression, whereas other, neuroactive small molecules including the epilepsy drug lacosamide and the natural brain metabolite lanthionine ketimine appear to bind CRMP2 directly with concomitant affects on neural structure. These findings constitute proofs-of-concept that pharmacological manipulation of CRMP2 is possible and hence, may offer new opportunities for therapy development against certain neurological diseases.

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Section: Structure Expression Pattern and Protein Interactome Of Dpmentioning

confidence: 99%

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

et al. 2011

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“…Cystathionine is needed to synthesize cysteine (5), the rate-limiting substrate for GSH synthesis (6,7). In mammalian brain, lanthionine, a thioether analog of cysteine, is thought to be produced by CBS (8,9) and converted to the unusual cyclic thioether lanthionine ketimine, which also binds to LanCL1 (10), suggesting that LanCL1 may be involved in a CBS-mediated trans-sulfuration pathway.…”

mentioning

confidence: 99%

Lanthionine Synthetase C-like Protein 1 Interacts with and Inhibits Cystathionine β-Synthase

Zhong

Wang

Peng

et al. 2012

Journal of Biological Chemistry

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Background:The function of LanCL1 remains unknown. Cystathionine ␤-synthase (CBS) is important for GSH synthesis. Results: LanCL1 directly binds and inhibits CBS. Oxidative stress down-regulates the binding and increases CBS activity. Intervention in the binding exerts neuronal antioxidant defense. Conclusion: LanCL1 is a negative regulator of CBS and a sensor of oxidative stress. Significance: This study reveals a novel function of LanCL1 in CBS-mediated neuronal redox homeostasis.

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“…C4RIP [86] is an antagonist small peptide for the N-terminal domain of CRMP4b, which is the interactive region to RhoA and TBI-induced cell death [96,126]. Lanthionine ketamine (LK) and its synthetic cell-penetrating ester derivative, LK ester (LKE) [127], are endogenous sulfur amino acid metabolites that bind directly to CRMP2. While their role in CRMP2 phosphorylation remains unknown, LKE administration reduces CRMP2-tubulin affinity while enhancing CRMP2-neurofilament binding.…”

Section: Crmps In Inflammatory Cellsmentioning

confidence: 99%

“…WO 2014139539 A1). Interestingly, BMP signaling downstream to the transcription factor Smad1 has been shown to suppress the Decreased excitatory synaptic connectivity in posttraumatic epileptogenesis [125] and reduction in pain behavior in vivo [100] LKE CRMP2 Alters binding affinity of CRMP2 and its partners Suppressed inflammation in the AD model [127] Neuroprotection in the multiple sclerosis [128] and cerebral ischemia [129] C4RIP RhoA-CRMP4 binding Antagonizes the binding of RhoA and the N-terminus of CRMP4b…”

Section: Crmps In Inflammatory Cellsmentioning

confidence: 99%

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

2016

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Neurodegeneration in the adult mammalian central nervous system (CNS) is fundamentally accelerated by its intrinsic neuronal mechanisms, including its poor regenerative capacity and potent extrinsic inhibitory factors. Thus, the treatment of neurodegenerative diseases faces many obstacles. The degenerative processes, consisting of axonal/dendritic structural disruption, abnormal axonal transport, release of extracellular factors, and inflammation, are often controlled by the cytoskeleton. From this perspective, regulators of the cytoskeleton could potentially be a therapeutic target for neurodegenerative diseases and CNS injury. Collapsin response mediator proteins (CRMPs) are known to regulate the assembly of cytoskeletal proteins in neurons, as well as control axonal growth and neural circuit formation. Recent studies have provided some novel insights into the roles of CRMPs in several inhibitory signaling pathways of neurodegeneration, in addition to its functions in neurological disorders and CNS repair. Here, we summarize the roles of CRMPs in axon regeneration and its emerging functions in non-neuronal cells, especially in inflammatory responses. We also discuss the direct and indirect targeting of CRMPs as a novel therapeutic strategy for neurological diseases.

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Proteomic Identification of Binding Partners for the Brain Metabolite Lanthionine Ketimine (LK) and Documentation of LK Effects on Microglia and Motoneuron Cell Cultures

Cited by 75 publications

References 44 publications

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

Lanthionine Synthetase C-like Protein 1 Interacts with and Inhibits Cystathionine β-Synthase

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

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