Heparan sulfate deficiency in autistic postmortem brain tissue from the subventricular zone of the lateral ventricles

Department of Cell Biology and Physiology, University of North Carolina, 115 Mason Farm Road, Chapel Hill, NC 27599, USA.
Behavioural brain research (Impact Factor: 3.03). 01/2013; 243(1). DOI: 10.1016/j.bbr.2012.12.062
Source: PubMed


Abnormal cellular growth and organization have been characterized in postmortem tissue from brains of autistic individuals, suggestive of pathology in a critical neurogenic niche, the subventricular zone (SVZ) of the brain lateral ventricles (LV). We examined cellular organization, cell proliferation, and constituents of the extracellular matrix such as N-sulfated heparan sulfate (HS) and laminin (LAM) in postmortem brain tissue from the LV-SVZ of young to elderly individuals with autism (n=4) and age-matched typically developing (TD) individuals (n=4) using immunofluorescence techniques. Strong and systematic reductions in HS immunofluorescence were observed in the LV-SVZ of the TD individuals with increasing age. For young through mature, but not elderly, autistic pair members, HS was reduced compared to their matched TDs. Cellular proliferation (Ki67+) was higher in the autistic individual of the youngest age-matched pair. These preliminary data suggesting that HS may be reduced in young to mature autistic individuals are in agreement with previous findings from the BTBR T+tf/J mouse, an animal model of autism; from mice with genetic modifications reducing HS; and with genetic variants in HS-related genes in autism. They suggest that aberrant extracellular matrix glycosaminoglycan function localized to the subventricular zone of the lateral ventricles may be a biomarker for autism, and potentially involved in the etiology of the disorder.

Download full-text


Available from: Brandon L Pearson, Aug 02, 2015
1 Follower
35 Reads
  • Source
    • "These genetic studies revealed that HS is necessary for the specific functioning of certain brain structures, such as the cerebellum and the olfactory bulbs, cortical neurogenesis, and a variety of axon path-finding processes (Kantor et al. 2004). Pearson et al. (2013) suggest that aberrant function extracellular matrix glycosaminoglycan (GAG) localized to the subventricular zone of the lateral ventricles may be a biomarker for ASD, and potentially involved in the etiology of the disorder. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autism research continues to receive considerable attention as the options for successful management are limited. The understanding of the autism spectrum disorder (ASD) etiology has now progressed to encompass genetic, epigenetic, neurological, hormonal, and environmental factors that affect outcomes for patients with ASD. Glycosaminoglycans (GAGs) are a family of linear, sulfated polysaccharides that are associated with central nervous system (CNS) development, maintenance, and disorders. Proteoglycans (PG) regulate diverse functions in the central nervous system. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major GAGs present in the PGs of the CNS. As neuroscience advances, biochemical treatments to correct brain chemistry become better defined. Nutrient therapy can be very potent and has minimal to no side effects, since no molecules foreign to the body are needed. Given GAGs are involved in several neurological functions, and that its level can be somewhat modulated by the diet, the present study aimed to evaluate the role of GAGs levels in ASD symptoms. Both tGAG and its different fractions were evaluated in the urine of ASD and healthy control childrens. As levels differed between groups, a second trial was conduted evaluating if diet could reduce tGAG levels and if this in turn decrease ASD symptoms. The present study found that tGAG concentration was significantly higher in the urine of children with ASD compared to healthy control children and this was also evident in all GAG fractions. Within groups (controls and ASD), no gender differences in GAG excretion were found. The use of a 90 days elimination diet (casein-free, special carbohydrates, multivitamin/mineral supplement), had major effects in reducing urinary tGAG excretion in children with ASD.
    Metabolic Brain Disease 10/2015; DOI:10.1007/s11011-015-9745-2 · 2.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multisystem interactions are well established in neurological disorders, in spite of conventional views that only the central nervous system (CNS) is impacted. We review evidence for mutual interactions between the immune and nervous systems and show how these seem to be implicated in the origin and progression of nervous system disorders. Well-established immune system triggers leading to autoimmune reactions are considered. Of these, aluminum, a known neurotoxicant, may be of particular importance. We have demonstrated elsewhere that aluminum has the potential to induce damage at a range of levels in the CNS leading to neuronal death, circuit malfunction, and ultimately system failure. Aluminum is widely used as an adjuvant in various vaccine formulations and has been implicated in a multisystem disorder termed “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA). The implications of aluminum-induced ASIA in some disorders of the CNS are considered. We propose a unified theory capturing a progression from a local response to a systemic response initiated by disruption of water-based interfaces of exposed cells.
    Immunome Research 01/2013; 9(069):1. DOI:10.4172/1745-7580.1000069
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proteoglycans (PGs) regulate diverse functions in the central nervous system (CNS) by interacting with a number of growth factors, matrix proteins, and cell sur-face molecules. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major glycosaminoglycans present in the PGs of the CNS. The functionality of these PGs is to a large extent dictated by the fine sulfation patterns present on their glycosaminoglycan (GAG) chains. In the past 15 years, there has been a significant expansion in our knowledge on the role of HS and CS chains in various neurological processes, such as neuronal growth, regen-eration, plasticity, and pathfinding. However, defining the relation between distinct sulfation patterns of the GAGs and their functionality has thus far been difficult. With the emergence of novel tools for the synthesis of defined GAG structures, and techniques for their characterization, we are now in a better position to explore the structure-function relation of GAGs in the context of their sulfation patterns. In this review, we discuss the importance of GAGs on CNS development, injury, and disorders with an emphasis on their sulfation patterns. Finally, we outline several GAG-based therapeutic strategies to exploit GAG chains for ameliorating various CNS disorders.
    Biomolecular concepts 03/2013; 4(3):233-257. DOI:10.1515/bmc-2012-0042
Show more