Age-Related Decline in Gangliosides GM1 and GD1a in Non-CNS Tissues of Normal Mice: Implications for Peripheral Symptoms of Parkinson's Disease.

The purpose of this study was to determine whether the age-related decline in a-series gangliosides (especially GM1), shown to be a factor in the brain-related etiology of Parkinson's disease (PD), also pertains to the peripheral nervous system (PNS) and aspects of PD unrelated to the central nervous system (CNS). Following Svennerholm's demonstration of the age-dependent decline in a-series gangliosides (both GM1 and GD1a) in the human brain, we previously demonstrated a similar decline in the normal mouse brain. The present study seeks to determine whether a similar a-series decline occurs in the periphery of normal mice as a possible prelude to the non-CNS symptoms of PD.

Systemic deficiency of GM1 ganglioside in Parkinson's disease tissues and its relation to the disease etiology.

Following our initial reports on subnormal levels of GM1 in the substantia nigra and occipital cortex of Parkinson's disease (PD) patients, we have examined additional tissues from such patients and found these are also deficient in the ganglioside. These include innervated tissues intimately involved in PD pathology such as colon, heart and others, somewhat less intimately involved, such as skin and fibroblasts. Finally, we have analyzed GM1 in peripheral blood mononuclear cells, a type of tissue apparently with no direct innervation, and found those too to be deficient in GM1.

Mice deficient in GM1 manifest both motor and non-motor symptoms of Parkinson's disease; successful treatment with synthetic GM1 ganglioside.

Parkinson's disease (PD) is a major neurodegenerative disorder characterized by a variety of non-motor symptoms in addition to the well-recognized motor dysfunctions that have commanded primary interest. We previously described a new PD mouse model based on heterozygous disruption of the B4galnt1 gene leading to partial deficiency of the GM1 family of gangliosides that manifested several nigrostriatal neuropathological features of PD as well as movement impairment. We now show this mouse also suffers three non-motor symptoms characteristic of PD involving the gastrointestinal, sympathetic cardiac, and cerebral cognitive systems.

Parkinson's disease recovery by GM1 oligosaccharide treatment in the B4galnt1 mouse model.

Given the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1 mice, a model of sporadic Parkinson's disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson's phenotype expressed by the B4galnt1 mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins.

Gangliosides of the Nervous System.

This review begins by attempting to recount some of the pioneering discoveries that first identified the presence of gangliosides in the nervous system, their structures and topography. This is presented as prelude to the current emphasis on physiological function, about which much has been learned but still remains to be elucidated. These areas include ganglioside roles in nervous system development including stem cell biology, membranes and organelles within neurons and glia, ion transport mechanisms, receptor modulation including neurotrophic factor receptors, and importantly the pathophysiological role of ganglioside aberrations in neurodegenerative disorders.

Gangliosides, α-Synuclein, and Parkinson's Disease.

This review addresses the role of α-synuclein (αSyn) in the etiopathology of Parkinson's disease (PD), with emphasis on its interaction with GM1 ganglioside. We begin with a brief review of some of the milestone discoveries that helped to elucidate PD neuropathology, including the fibrous inclusions of Lewy that characterize the degenerating dopaminergic neurons of the substantia nigra and the presence of αSyn as a major constituent of these Lewy bodies and neurites. This enabled Braak et al.

Functional interplay between ganglioside GM1 and cross-linking galectin-1 induces axon-like neuritogenesis via integrin-based signaling and TRPC5-dependent Ca²⁺ influx.

Axon-like neuritogenesis in neuroblastoma (NG108-15) cells and primary cerebellar granular neurons is furthered by the presence of ganglioside GM1. We describe here that galectin-1 (Gal-1), a homobivalent endogenous lectin, is an effector by cross-linking the ganglioside and its associated glycoprotein α5 β1 -integrin. The thereby triggered signaling cascade involves autophosphorylation of focal adhesion kinase and activation of phospholipase Cγ and phosphoinositide-3 kinase.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice.

Our previous studies have shown accumulation of GM2 ganglioside during ethanol-induced neurodegeneration in the developing brain, and GM2 elevation has also been reported in other brain injuries and neurodegenerative diseases. Using GM2/GD2 synthase KO mice lacking GM2/GD2 and downstream gangliosides, the current study explored the significance of GM2 elevation in WT mice. Immunohistochemical studies indicated that ethanol-induced acute neurodegeneration in postnatal day 7 (P7) WT mice was associated with GM2 accumulation in the late endosomes/lysosomes of both phagocytic microglia and increased glial fibrillary acidic protein (GFAP)-positive astrocytes.

The multi-tasked life of GM1 ganglioside, a true factotum of nature.

GM1 ganglioside occurs widely in vertebrate tissues, where it exhibits many essential functions, both in the plasma membrane and intracellular loci. Its essentiality is revealed in the dire consequences resulting from genetic deletion. This derives from its key roles in several signalosome systems, characteristically located in membrane rafts, where it associates with specific proteins that have glycolipid-binding domains.

GDNF signaling implemented by GM1 ganglioside; failure in Parkinson's disease and GM1-deficient murine model.

GDNF is indispensible for adult catecholaminergic neuron survival, and failure of GDNF signaling has been linked to loss of dopaminergic neurons in Parkinson's disease (PD). This study demonstrates attenuated GDNF signaling in neurons deficient in ganglio-series gangliosides, and restoration of such signaling with LIGA20, a membrane permeable analog of GM1. GM1 is shown to associate in situ with GFRα1 and RET, the protein components of the GDNF receptor, this being necessary for assembly of the tripartite receptor complex.

Glycobiology of ion transport in the nervous system.

The nervous system is richly endowed with large transmembrane proteins that mediate ion transport, including gated ion channels as well as energy-consuming pumps and transporters. Transport proteins undergo N-linked glycosylation which can affect expression, location, stability, and function. The N-linked glycans of ion channels are large, contributing between 5 and 50 % of their molecular weight.

Deficiency of ganglioside GM1 correlates with Parkinson's disease in mice and humans.

Several studies have successfully employed GM1 ganglioside to treat animal models of Parkinson's disease (PD), suggesting involvement of this ganglioside in PD etiology. We recently demonstrated that genetically engineered mice (B4galnt1(-/-) ) devoid of GM1 acquire characteristic symptoms of this disorder, including motor impairment, depletion of striatal dopamine, selective loss of tyrosine hydroxylase-expressing neurons, and aggregation of α-synuclein. The present study demonstrates similar symptoms in heterozygous mice (HTs) that express only partial GM1 deficiency.

Beyond glycoproteins as galectin counterreceptors: tumor-effector T cell growth control via ganglioside GM1 [corrected].

Glycoprotein glycan chains, by virtue of structure, topology of presentation and connection to signal-inducing units, are functional galectin counterreceptors. As example, cross-linking of the α(5)β(1) integrin by galectin-1 on carcinoma cells leads to G(1) arrest or anoikis. Contact-dependent switching from proliferation to differentiation in cultured neuroblastoma cells (SK-N-MC) also utilizes galectin-1.

Ganglioside GM1 deficiency in effector T cells from NOD mice induces resistance to regulatory T-cell suppression.

Objective: To detect GM1 deficiency and determine its role in effector T cells (Teffs) from NOD mice in establishing resistance to regulatory T-cell (Treg) suppression.

Research Design And Methods: CD4(+) and CD8(+) Teffs were isolated from spleens of prediabetic NOD mice for comparison with similar cells from Balb/c, C57BL/6, and NOR mice. GM1 was quantified with thin-layer chromatography for total cellular GM1 and flow cytometry for cell-surface GM1.

Mice lacking major brain gangliosides develop parkinsonism.

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder that affects nearly 1% of the global population aged 65 and older. Whereas palliative treatments are in use, the goal of blocking progression of motor and cognitive disability remains unfulfilled. A better understanding of the basic pathophysiological mechanisms underlying PD would help to advance that goal.

New findings on nuclear gangliosides: overview on metabolism and function.

GM1 and GD1a gangliosides occur in both membranes of the nuclear envelope (NE) together with two isoforms of neuraminidase. The Neu3 isoform of neuraminidase occurs in the inner membrane of the NE and Neu1 in the outer membrane. Both isoforms convert GD1a to GM1 within the respective membranes.

In search of a solution to the sphinx-like riddle of GM1.

Among the many glycoconjugates contributing to the sugar code, gangliosides have drawn special attention owing to their predominance as the major sialoglycoconjugate category within the nervous system. However, their occurrence, albeit at lower levels, appears ubiquitous in vertebrate cells and even some invertebrate tissues. Now that over 100 gangliosides have been structurally characterized, their diverse physiological functions constitute a remaining enigma.

Sialidase occurs in both membranes of the nuclear envelope and hydrolyzes endogenous GD1a.

Previous reports indicated the presence of both gangliosides and sialidase in the nuclear envelope (NE) of primary neurons and the NG108-15 neural cell line. GM1, one of the major gangliosides of this membrane, was shown to be tightly associated with a sodium-calcium exchanger in the inner membrane of the NE and to potentiate exchanger activity. GD1a was the other major ganglioside detected in the NE and, like GM1, occurs in both inner and outer membranes.

Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum.

The inner membrane of the nuclear envelope (NE) was previously shown to contain a Na/Ca exchanger (NCX) tightly linked to GM1 ganglioside that mediates transfer of nucleoplasmic Ca(2+) to the NE lumen and constitutes a cytoprotective mechanism. This transfer was initially observed with isolated nuclei and is now demonstrated in living cells in relation to subcellular Ca(2+) dynamics. Four cell lines with varying expression of NCX and GM1 in the NE were transfected with cameleon-fluorescent Ca(2+) indicators genetically targeted to NE/endoplasmic reticulum (ER) and nucleoplasm to monitor [Ca(2+)](ne/er) and [Ca(2+)](n) respectively.

Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis.

Several animal autoimmune disorders are suppressed by treatment with the GM1 cross-linking units of certain toxins such as B subunit of cholera toxin (CtxB). Due to the recent observation of GM1 being a binding partner for the endogenous lectin galectin-1 (Gal-1), which is known to ameliorate symptoms in certain animal models of autoimmune disorders, we tested the hypothesis that an operative Gal-1/GM1 interplay induces immunosuppression in a manner evidenced by both in vivo and in vitro systems. Our study of murine experimental autoimmune encephalomyelitis (EAE) indicated suppressive effects by both CtxB and Gal-1 and further highlighted the role of GM1 in demonstrating enhanced susceptibility to EAE in mice lacking this ganglioside.

Myelin lipid abnormalities in the aspartoacylase-deficient tremor rat.

The high concentration of N-acetylaspartate (NAA) in neurons of the central nervous system and its growing clinical use as an indicator of neuronal viability has intensified interest in the biological function of this amino acid derivative. The biomedical relevance of such inquiries is highlighted by the myelin-associated pathology of Canavan disease, an inherited childhood disorder resulting from mutation of aspartoacylase (ASPA), the NAA-hydrolyzing enzyme. This enzyme is known to be localized in oligodendrocytes with bimodal distribution in cytosol and the myelin sheath, and to produce acetyl groups utilized in myelin lipid synthesis.

Nuclear sphingolipids: metabolism and signaling.

Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes.

GM1 in the nuclear envelope regulates nuclear calcium through association with a nuclear sodium-calcium exchanger.

The inner membrane of the nuclear envelope (NE) of neurons and other cells has been shown to contain GM1 tightly associated with a Na(+)/Ca(2+) exchanger (NCX) whose activity it potentiates in mediating transfer of Ca(2+) from nucleoplasm to the NE lumen. This is consistent with localization of the NCX/GM1 complex in the inner membrane of the NE. NCXs of the plasma membrane, in contrast, appear to bind GM1 much less avidly.

Induction of calcium influx through TRPC5 channels by cross-linking of GM1 ganglioside associated with alpha5beta1 integrin initiates neurite outgrowth.

Previous studies demonstrated that cross-linking of GM1 ganglioside with multivalent ligands, such as B subunit of cholera toxin (CtxB), induced Ca2+ influx through an unidentified, voltage-independent channel in several cell types. Application of CtxB to undifferentiated NG108-15 cells resulted in outgrowth of axon-like neurites in a Ca2+ influx-dependent manner. In this study, we demonstrate that CtxB-induced Ca2+ influx is mediated by TRPC5 channels, naturally expressed in these cells and primary neurons.

Sodium-calcium exchangers in the nucleus: an unexpected locus and an unusual regulatory mechanism.

Whereas sodium-calcium exchangers (NCXs) have long been recognized as plasma membrane constituents that serve to maintain homeostatic concentrations of Ca2+ in the cytoplasm, they were recently shown to also occur in the nuclear envelope (NE) of neural and other cells where they function to regulate nuclear Ca2+. A unique feature of NCXs in the NE is their high-affinity binding to GM1 ganglioside, this association being required for optimal exchanger activity. The NCX-GM1 complex occurs in the inner membrane of the NE and transfers Ca2+ from the nucleoplasm to the NE lumen.