Identification of a critical sulfation in chondroitin that inhibits axonal regeneration

Pearson, Craig S; Mencio, Caitlin; Barber, Amanda C.; Martin, Keith R; Geller, Herbert M.

doi:10.7554/elife.37139

Cited by 66 publications

(52 citation statements)

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“…Analysis of total extracellular CSPG with CS-56 at early stages of PNN loss, which generally labels CSPGs excluded from PNNs e.g. those found in glial scars [ 54 , 55 ], revealed significant increases in the subiculum but not visual cortex ( p <0.05, p = 0.0818) of 5xFAD mice (Fig. S2A-C).…”

Section: Resultsmentioning

confidence: 99%

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

et al. 2020

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Background Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial. Methods Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia. Findings Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence. Interpretation We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain. Funding The NIH (NIA, NINDS) and the Alzheimer's Association.

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Section: Resultsmentioning

confidence: 99%

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

et al. 2020

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“…Increases in chondroitin sulfate and the chondroitin sulfate proteoglycan versican were identified in more aggressive prostate cancers . Increased C4S has significant consequences for transcription, signaling, metabolism, and proliferation in the prostate and in other tissues …”

Section: Introductionmentioning

confidence: 99%

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

2019

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Background:In tissue microarrays, immunostaining of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) was less in recurrent prostate cancers and in cancers with higher Gleason scores. In cultured prostate stem cells, decline in ARSB increased Wnt signaling through effects on Dickkopf Wnt Signaling Pathway Inhibitor (DKK)3. The effects of androgen exposure on ARSB and the impact of decline in ARSB on Wnt signaling in prostate tissue were unknown.Methods: Epithelial and stromal tissues from malignant and normal human prostate were obtained by laser capture microdissection. mRNA expression of ARSB, galactose-6-sulfate-sulfatase (GALNS) and Wnt-signaling targets was determined by QPCR.Non-malignant human epithelial and stromal prostate cells were grown in tissue culture, including two-cell layer cultures. ARSB was silenced by specific siRNA, and epithelial cells were treated with stromal spent media following treatment with IWP-2, an inhibitor of Wnt secretion, and by exogenous recombinant human Wnt3A.Promoter methylation was detected using specific DKK3 and ARSB promoter primers.The effects of DHT and of ARSB overexpression on DKK expression were determined. Cell proliferation was assessed by BrdU incorporation.Results: Normal stroma showed higher expression of vimentin, ARSB, and Wnt3A than epithelium. Normal epithelium had higher expression of E-cadherin, galactose 6sulfate-sulfatase (GALNS), and DKK3 than stroma. In malignant epithelium, expression of ARSB and DKK3 declined, and expression of GALNS and Wnt signaling targets increased. In cultured prostate epithelial cells, Wnt-mediated signaling was greatest when ARSB was silenced and cells were exposed to exogenous Wnt3A. Exposure to 5α-dihydrotestosterone (DHT) increased ARSB and DKK3 promoter rmethylation, and effects of DHT on DKK3 expression were reversed when ARSB was overexpressed. Conclusions: Androgen-induced declines in ARSB and DKK3 may contribute to prostate carcinogenesis by sustained activation of Wnt signaling in prostate epithelium in response to stromal Wnt3A. K E Y W O R D S arylsulfatase B, DHT, DKK3, methylation, Wnt3A 2 | BHATTACHARYYA ET AL. 690 1 | INTRODUCTION Chondroitin sulfates are present in significant amounts throughout mammalian tissues, including epithelium and stroma in all organs. With other glycosaminoglycans, including heparin, heparan sulfate, keratan sulfate, dermatan sulfate, and hyaluronan, and by interactions with collagen, protein components of proteoglycans, and structural proteins, they form the framework that is necessary for proper tissue structure and function. The chondroitin sulfatase arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes 4-sulfates from the non-reducing end of chondroitin 4-sulfate (C4S) and is required for the subsequent degradation of C4S by glycosidases. 1-3 The chondroitin sulfatase galactose 6-sulfate-sulfatase (GALNS; N-acetylgalactosamine-6-sulfatase) removes 6-sulfate groups from chondroitin 6-sulfate (C6S) or chondroitin 4,6-disulfate (chondroitin sulfate E),...

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“…In a tau model of neurodegeneration, plasticity was restored with an antibody against 4-sulfated GAG (Yang S. et al, 2017 ). Our investigation of changes in CS sulfation patterns following both spinal cord injury (Wang et al, 2008 ) and optic nerve crush (Pearson et al, 2018 ) have found a large increase in 4-sulfated GAG chains in the injury site, with little or no change in 6-sulfated GAG chains. In culture, the production of 4-sulfated, but not 6-sulfated GAG chains were increased in astrocytes after treatment with TGF-β (Wang et al, 2008 ).…”

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confidence: 85%

“…As noted above, 4-sulfated CS is associated with inhibition of axonal outgrowth (Wang et al, 2008;Yoo et al, 2013;Pearson et al, 2018). Both CS-E and DS, which bind to both RPTPσ and NgR1 and 3, contain 4-S GalNAc, but how 4-sulfation affects binding of these sugars to these receptors is yet to be determined.…”

mentioning

confidence: 95%

“…ARSB selectively removes 4-sulfation specifically at the non-reducing end of CS GAG chains (Matalon et al, 1974 ). In culture, ARSB was able to increase hippocampal neurite outgrowth on astrocytes treated with either TGF-β (Pearson et al, 2018 ) or ethanol (Zhang et al, 2014 ). This efficacy of ARSB has been confirmed in vivo , where it was able to improve locomotor function after spinal cord injury (Yoo et al, 2013 ), as well as optic nerve regeneration after a crush (Pearson et al, 2018 ).…”

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confidence: 99%

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Role of Chondroitin Sulfation Following Spinal Cord Injury

Hussein

Mencio

Katagiri

et al. 2020

Front. Cell. Neurosci.

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Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules-primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)-which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.

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Identification of a critical sulfation in chondroitin that inhibits axonal regeneration

Cited by 66 publications

References 52 publications

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

Role of Chondroitin Sulfation Following Spinal Cord Injury

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