Ablation of Keratan Sulfate Accelerates Early Phase Pathogenesis of ALS

Abstract

Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1G93A mice and GlcNAc6ST-1−/− mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1G93AGlcNAc6ST-1−/− mice exhibited a significantly shorter lifespan than SOD1G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1G93A mice, while this enhancement was attenuated in SOD1G93AGlcNAc6ST-1−/− mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1G93AGlcNAc6ST-1−/− mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.

Keratan sulfate: An up-to-date review

“…In ALS, KS expression is seen exclusively at a subpopulation of microglia of the wild-type mice. Its detection is reported to be only at early stages of the disease [23]. As opposed to the normal mice which showed a transient enhancement of microglia markers, this enhancement was considerably attenuated in GlcNAc6S −/− mutant mice.…”

“…[23] are expectedly found at increased levels. The low amounts of KS in this pathology can make the ill condition even worst.…”

“…It is characterized by muscle spasticity, rapidly progressive weakness due to muscle atrophy, difficulty in speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea). Hirano and coworkers have recently made the connection between the lack of KS and the increased development of ALS pathogenesis at its early phase [23]. The investigators have used comparatively both wild-type ALS-induced and GlcNAc6S −/− ALS-induced mice models, knocked-out just at their tissues of the central nervous system.…”

“…In all, Ref. [23] has indicated that KS plays an indispensable suppressive role in the early stages of development of the ALS pathogenesis. Although no tests of KS administration have been done, the authors still suggest the possibility of taking KS as a future drug candidate in therapeutic interventions against ALS disease.…”

“…Since KS is inadequately deposited in patients of MPS IVA due to dysfunction of the galactose 6-sulfate sulfatase, it has been reported that measurements of the accumulated mutation on the gene GALNS of this enzyme, as well as the plasma and blood KS concentrations, are quite useful to the diagnostic of the severity levels of this disease. Curiously, all works available in the literature between 2010 and 2014 concerning the beneficial roles of KS to health or as target molecule for therapeutic purpose come from Japan [19][20][21][22][23]. These works have been revisited in the second topic (Section 3) of this review, and are describing the potential roles of KS in suppressing the cartilage damage, in combating inflammation process, in reducing radiation-induced apoptosis of lymphoma cells, and in suppressing early phase pathogenesis of ALS.…”