Cartilage Acidic Protein–1B (LOTUS), an Endogenous Nogo Receptor Antagonist for Axon Tract Formation

Sato, Yasufumi; Iketani, Masumi; Kikuchi, Yuji; Yamaguchi, Megumi; Yamashita, Naoya; Nakamura, Fumio; Arie, Yuko; Kawasaki, Tadahiro; Hirata, Tatsumi; Abe, Takaya; Kanazawa, Hiroshi; Strittmatter, Stephen M.; Goshima, Yoshio; Takei, Kohtaro

doi:10.1126/science.1204144

Cited by 90 publications

(103 citation statements)

References 34 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Moreover, these biomarkers are not directly related to the pathogenesis of MS. Therefore, a new CSF biomarker is required for accurate diagnosis, appropriate therapy, comprehension of pathogenesis, and the development of new therapeutic strategies in MS. 1 Lateral olfactory tract usher substance is a neuronal molecule 8 and our data showing a good correlation between variations in LOTUS concentrations and disease dynamics strongly suggest that LOTUS may be a useful biomarker for disease activity and prognosis for both patients with RRMS and patients with SPMS. From a clinical point of view, our findings provide new avenues for LOTUS as a useful biomarker and for understanding the pathogenesis of MS.…”

Section: Discussionmentioning

confidence: 74%

Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis

et al. 2015

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Although multiple sclerosis (MS) is generally considered an autoimmunedemyelinating disorder of the central nervous system, axonal degeneration through Nogo receptor-1 signaling was recently recognized as an important pathological feature. Our previous identification of lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor-1 antagonist, prompted us to analyze the relationship between LOTUS levels of cerebrospinal fluid and the clinical course of MS to evaluate whether LOTUS could be a useful biomarker for MS. OBJECTIVE To examine variations in LOTUS concentrations in the cerebrospinal fluid of patients with MS in accordance with their clinical course. DESIGN, SETTING, AND PARTICIPANTS Cerebrospinal fluid samples were obtained retrospectively from normal controls (NCs; n = 27) and patients with MS (n = 40), amyotrophic lateral sclerosis (n = 22), and multiple system atrophy (n = 10) between January 1, 2008, and January 1, 2014. Patients with MS were divided into relapsing-remitting MS (RRMS; n = 30) and secondary progressive MS (n = 10). Patients with RRMS were further divided into relapse and remission groups. MAIN OUTCOMES AND MEASURESThe LOTUS concentration in cerebropsinal fluid was quantitatively detected by immunoblotting using a specific LOTUS antibody and the concentrations compared in accordance with the patients' clinical course, such as remission and relapse groups in RRMS and secondary progressive MS. RESULTSThe mean (SD) cerebrospinal fluid LOTUS concentration in the relapse group of RRMS (9.3 [3.6] μg/dL) was lower than that of NCs (19.2 [4.7] μg/dL; P < .001) whereas the level in the remission group of RRMS (19.6 [5.8] μg/dL) was similar to that of NCs. The LOTUS concentration in SPMS (6.7 [1.4] μg/dL; P < .001) was lower than that of NCs and the remission group of RRMS. The LOTUS levels in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple system atrophy, were normal.CONCLUSIONS AND RELEVANCE Variations in LOTUS concentrations were correlated with disease activity in MS. Therefore, LOTUS concentration may be useful as a possible biomarker for MS. Low LOTUS concentrations may be possibly involved in Nogo receptor-1 signaling, which may induce axonal degeneration in the relapse phase of RRMS and secondary progressive MS.

show abstract

Section: Discussionmentioning

confidence: 74%

Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…PirB, a receptor for myelin proteins that is active in many contexts with NgR1 (56), is remarkable in its 83× and 91× induction in the early stages of white matter stroke in young adult and aged brain, respectively. Endogenous inhibitors of NgR1 signaling, including LGl1, LOTUS, and ADAM22 (34,35), are down-regulated after white matter stroke in the young adult and further down-regulated in the aged brain white matter after stroke. Many of these NgR1 ligands act through this receptor to decrease OPC differentiation, placing this signaling system as a candidate mediator for the differentiation block in OPC responses after white matter stroke.…”

Section: Discussionmentioning

confidence: 99%

“…There is an age effect observed in that aggrecan, versican, syndecan 1, and glypican 2 are induced to a greater extent in aged stroke. Three negative regulators of NgR1 signaling, leucine-rich glioma inactivated 1 (Lgi1), cartilage acidic protein-1B (LOTUS), and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) (34,35), are decreased after white matter stroke, with a greater reduction in aged white matter stroke. Interestingly, white matter stroke reduces levels of NgR1 coreceptor Lingo1 and impressively up-regulates a second myelin protein receptor, paired Ig-like receptor B (PirB) (Fig.…”

Section: Svz Does Not Contribute To Generation Of New Opcs After Whitmentioning

confidence: 99%

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

Sözmen

Rosenzweig

Llorente

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

100

115

View full text Add to dashboard Cite

White matter stroke is a distinct stroke subtype, accounting for up to 25% of stroke and constituting the second leading cause of dementia. The biology of possible tissue repair after white matter stroke has not been determined. In a mouse stroke model, white matter ischemia causes focal damage and adjacent areas of axonal myelin disruption and gliosis. In these areas of only partial damage, local white matter progenitors respond to injury, as oligodendrocyte progenitors (OPCs) proliferate. However, OPCs fail to mature into oligodendrocytes (OLs) even in regions of demyelination with intact axons and instead divert into an astrocytic fate. Local axonal sprouting occurs, producing an increase in unmyelinated fibers in the corpus callosum. The OPC maturation block after white matter stroke is in part mediated via Nogo receptor 1 (NgR1) signaling. In both aged and young adult mice, stroke induces NgR1 ligands and down-regulates NgR1 inhibitors during the peak OPC maturation block. Nogo ligands are also induced adjacent to human white matter stroke in humans. A Nogo signaling blockade with an NgR1 antagonist administered after stroke reduces the OPC astrocytic transformation and improves poststroke oligodendrogenesis in mice. Notably, increased white matter repair in aged mice is translated into significant poststroke motor recovery, even when NgR1 blockade is provided during the chronic time points of injury. These data provide a perspective on the role of NgR1 ligand function in OPC fate in the context of a specific and common type of stroke and show that it is amenable to systemic intervention to promote recovery.repair | oligodendrocyte progenitor cell | oligodendrocyte | subventricular zone | astrocyte I schemic stroke in the adult brain occurs in two basic forms. Occlusion of large brain arteries produces stroke that spans brain areas, including gray matter (cortex, striatum) and white matter regions. Stroke in small brain vessels often occurs only in subcortical white matter regions, and these infarcts account for up to 25% of all stroke. The incidence of white matter stroke is age-associated and is the second leading cause of dementia (1-3). The resulting infarcts are distinct from large artery stroke, not only in cause and location but also in progressive accumulation over time (1,3,4). Ischemic regions after white matter stroke grow, with progression of the damage even in the controlled conditions of a clinical trial (5). Importantly, the presence of white matter ischemic lesions closely correlates with abnormalities in cognition, balance, and gait and carries an increased risk of death (6, 7).Despite such clinical importance, white matter repair after white matter stroke is still relatively unknown, which is in part because most basic science studies of stroke focus on large artery infarcts, such as middle cerebral artery occlusions. Most of what is known about white matter repair is derived from studies in inflammatory or toxic injuries of white matter, such as multiple sclerosis (MS). In these nonstroke...

show abstract

“…In other words, LOTUS suppresses Nogo-NgR1 binding and Nogoinduced growth cone collapse. Further, it is found that a defasciculated LOT is present in LOTUS-deficient mice but not in mice lacking both LOTUS and NgR1 [93]. This result indicates that there might be some other mechanism taking part in the defasciculation of LOT.…”

Section: Migration and Distributionmentioning

confidence: 69%

New Insights into the Roles of Nogo-A in CNS Biology and Diseases

Sui

Zhang

et al. 2015

Neurochem Res

View full text Add to dashboard Cite

Nogos have become a hot topic for its well-known number Nogo-A's big role in clinical matters. It has been recognized that the expression of Nogo-A and the receptor NgR1 inhibit the neuron's growth after CNS injuries or the onset of the MS. The piling evidence supports the notion that the Nogo-A is also involved in the synaptic plasticity, which was shown to negatively regulate the strength of synaptic transmission. The occurrence of significant schizophrenia-like behavioral phenotypes in Nogo-A KO rats also added strong proof to this conclusion. This review mainly focuses on the structure of Nogo-A and its corresponding receptor-NgR1, its intra- and extra-cellular signaling, together with its major physiological functions such as regulation of migration and distribution and its related diseases like stroke, AD, ALS and so on.

show abstract

Cartilage Acidic Protein–1B (LOTUS), an Endogenous Nogo Receptor Antagonist for Axon Tract Formation

Cited by 90 publications

References 34 publications

Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis

Association of Cerebrospinal Fluid Levels of Lateral Olfactory Tract Usher Substance (LOTUS) With Disease Activity in Multiple Sclerosis

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

New Insights into the Roles of Nogo-A in CNS Biology and Diseases

Contact Info

Product

Resources

About