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

Abstract

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.

LOTUS as a novel biomarker of multiple sclerosis

“…In addition to our previous findings regarding LOTUS function in mice, proteomic studies also suggested that LOTUS is present in human CSF . Using a biochemical approach, we successfully detected LOTUS in human CSF, and clarified the relationship between LOTUS levels in the CSF and clinical course or disease activity in MS …”

“…[3][4][5] In addition to our previous findings regarding LOTUS function in mice, proteomic studies also suggested that LOTUS is present in human CSF. 38 Using a biochemical approach, we successfully detected LOTUS in human CSF, and clarified the relationship between LOTUS levels in the CSF and clinical course or disease activity in MS. 39 In our analysis of CSF LOTUS levels, we initially divided the MS patients into RRMS and SPMS groups; those in the former group were classified into the relapse and remission groups according to findings of gadolinium-enhanced MRI lesions, medical history and clinical findings. LOTUS concentration was measured by quantitative immunoblotting.…”

Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS

“…Indeed, regenerating axons after SCI in LOTUS-TG mice overexpressed LOTUS; thus, the maintenance of LOTUS expression may be important for overcoming the influence of AGIs. However, the LOTUS concentration in cerebrospinal fluid (CSF) is markedly decreased in patients with cerebral infarction (unpublished data) and multiple sclerosis 29 compared with normal healthy controls. This phenomenon suggests that LOTUS expression in the CNS or secretion into the CSF is down-regulated by CNS damage and/or inflammation, although how LOTUS expression or secretion is down-regulated remains unknown.…”

LOTUS as an endogenous protein converting the adult central nervous system environment from nonpermissive to permissive for axonal regrowth after brain injury

“…The maintenance or increase of LOTUS expression might be important in order to overcome the influence of AGIs. In humans, in patients with cerebral infarction (Takahashi K, Tanaka F, Takei K, 2019), multiple sclerosis, and meningitis, the LOTUS concentration in the cerebrospinal fluid (CSF) significantly decreases compared with healthy people, indicating that LOTUS expression in the CNS or secretion into the CSF is downregulated by CNS damage and/or inflammation. However, how LOTUS expression or secretion decreases is still not determined.…”