Aberrant astrocytic expression of chondroitin sulfate proteoglycan receptors in a rat model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive and systemic loss of motor neurons with gliosis in the central nervous system (CNS) is a neuropathological hallmark of ALS. Chondroitin sulfate proteoglycans (CSPGs) are the major components of the extracellular matrix of the mammalian CNS, and they inhibit axonal regeneration physically by participating to form the glial scar. Recently, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related protein were discovered as CSPG receptors that play roles in inhibiting regeneration. Here we examined the expression of CSPG receptors in transgenic female rats overexpressing an ALS-linked mutant cytosolic Cu/Zn superoxide dismutase gene (SOD1). In contrast to controls, multiple immunofluorescence analyses revealed aberrant expression of CSPG receptors dominantly in reactive astrocytes, while PTPσ expression in neurons decreased in the spinal ventral horns of ALS transgenic rats. The aberrant and progressive astrocytic expression of CSPG receptors and reactive astrocytes themselves may be therapeutic targets for reconstructing a regeneration-supportive microenvironment under neurodegenerative conditions such as ALS.

Fibrotic Scar in Neurodegenerative Diseases

“…Astrocytosis has a particular impact on the disease, since it is characterized by a massive response of hypertrophic protoplasmic astrocytes surrounding degenerating motor neurons, and intense fibrotic astrocyte reactivity in the white matter ( 22 ). This process involves numerous molecular changes toward a reactive phenotype, such as production and secretion of pro-inflammatory cytokines, chemokines, and growth factors, in particular, IL-6, CXCL1, 10, 12, tumor necrosis factor-α, transforming growth factor β (TGFβ), nerve growth factor, interferon γ, prostaglandin D2 ( 23 ), as well as ECM components ( 24 , 25 ). During ALS, such activation could have the protective purpose to circumvent the degeneration spreading and to restrict inflammation by contrasting the infiltration of active immune cells into the injured tissue, preventing further tissue damage.…”

“…In addition to axon demyelination and loss of lipid structural order, these spectra differences account for proliferation and aggregation of branched CSPGs that, moreover, appear to be early events in the progression of the disease ( 29 ). Furthermore, CSPGs receptors are increased in reactive astrocytes from diseased rats, and this may contribute to further inhibition of neuronal regeneration, through a signaling mechanism induced by CSPGs ( 25 ). Accumulation of ECM is moreover testified by the downregulation of the ADAMTS-4 proteoglycanase activity, particularly at the end stage of the disease in SOD1-G93A mice lumbar spinal cord.…”

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

“…Four biochemical pathways seemed to represent the most consistent changes at a proteomic level: metabolism of carbohydrates (p= 0.0099), glycosaminoglycans (GAGs) metabolism, lysosome (p= 0.0015), synthesis of phosphatidic acid (p= 0.0184) and wnt signalling pathway (p= 0.0337). It has been shown that GAGs are involved in protein aggregation and prion diffusion ( [36][37][38][39][40][41][42][43][44] ). Lysosome activity changes were described in ALS caused by the C9orf72 gene repeat expansions ( [45][46][47][48][49] ), while synthesis of PA is linked to all types of phospholipids, including phosphatidylcholine and phosphatidylethanolamine that have been linked to ALS and prion disease pathogenesis ( 50,51 ).…”

Analysis of Circulating Protein Aggregates Reveals Pathological Hallmarks of Amyotrophic Lateral Sclerosis

“…We identi ed 48 proteins ( Supplementary Table 8) from which we could highlight four biochemical pathways: metabolism of carbohydrates (p = 0.0099), glycosaminoglycans (GAGs) metabolism, lysosome (p = 0.0015), synthesis of phosphatidic acid (PA; p = 0.0184) and wnt signalling pathway (p = 0.0337). GAGs are involved in protein aggregation and prion diffusion (Ancsin, 2003;DeWitt, Richey, Praprotnik, Silver, & Perry, 1994;Forostyak et al, 2014;Foyez et al, 2015;Hirano et al, 2013;Holmes et al, 2013;Nishitsuji, 2018;Sarrazin, Lamanna, & Esko, 2011;Shijo et al, 2018). Lysosome activity changes have been described in ALS caused by the C9orf72 gene repeat expansions (Cipolat Mis, Brajkovic, Frattini, Di Fonzo, & Corti, 2016;Sasaki, 2011;Shi et al, 2018;Song, Guo, Liu, & Tang, 2012;Sullivan et al, 2016), while synthesis of PA and related phospholipids, including phosphatidylcholine and phosphatidylethanolamine, have been linked to ALS and prion disease pathogenesis (Blasco et al, 2017;Supattapone, 2012).…”