The raft-associated protein MAL is required for maintenance of proper axon–glia interactions in the central nervous system

Abstract

The myelin and lymphocyte protein (MAL) is a tetraspan raft-associated proteolipid predominantly expressed by oligodendrocytes and Schwann cells. We show that genetic ablation of mal resulted in cytoplasmic inclusions within compact myelin, paranodal loops that are everted away from the axon, and disorganized transverse bands at the paranode–axon interface in the adult central nervous system. These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered. Initial formation of paranodal regions appeared normal, but abnormalities became detectable when MAL started to be expressed. Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts. Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.

The myelin-pathogenesis puzzle in schizophrenia: a literature review

“…139 Novak reevaluated the results of her previous investigation, using a more accurate method, a larger set of matched samples, and found an upregulation of the isoform Nogo C in schizophrenia. 140 Convergent evidence for the role of the Nogo gene in schizophrenia also comes from 111 Mediates oligo-oligodendrite and oligo-neuron adhesion 111 Provides a trophic signal to oligodendrites, without which oligodendroglial deterioration occurs 101 Regulates the properties of sodium channels at the nodes of Ranvier 111 MAG protein binds to the Nogo-66 receptor and inhibits axonal growth in vitro 112 MAG-deficient mice show delayed myelination and hypomyelination, but the latter is not associated with a loss of oligodendrites 111 MAG-deficient mice demonstrate an age-dependent dysfunction in myelin 98,111 Downregulation of the MAG protein has been shown at anterior frontal cortex 113 2 MAL 2qcen-13 Is expressed only when myelin compaction occurs 111 Is localized close to structural proteins (MBP and PLP1) 111 It may have functional contact with myelin glycosphingolipids 114 Organizes and stabilizes myelin via adhesion 114 Transgenic mice with increased MAL gene dosage revealed alterations of axon-glia interaction 115 MAL-deficient mice show defects in the maintenance of multiple domains of myelinated CNS axons, indicating aberrant protein trafficking 115 MAL-deficient mice demonstrate major alterations on the structural level (e.g. aberrant inclusions of cytoplasm within compact CNS myelin).…”

Rafts in oligodendrocytes: Evidence and structure–function relationship

“…The combination of biochemical studies with these photophysical, microfluorimetric methods will yield a better insight in the biological relevance of rafts in OLGs and help to come to a consensus on lipid rafts concerning their existence, size, lifetime and molecular organization. Pereyra et al 1988 4 to 6-weeks-old rat TX-100 0.5% 3 min RT Gillespie et al 1989 35-days-old mice TX-102 1% 30 min 4°C Taylor et al 2002 4-months-old mice: WT and MAL KO CHAPS na 30 min 4°C Schaeren-Wiemers et al 2004 Purified myelin Bovine brain E29 -E40 CHAPS 1.5% 30 min 4°C Debruin et al 2005 …”

“…Spinal cord Rat (WT or EAE) Lubrol WX 0.5% 30 min 4°C Maier et al 2005 Cx-32 Purified myelin 30-days-old rat brain TX-100 1% 30 min 4°C/37°C Kim and Pfeiffer 1999 30-days-old rat brain TX-100 1% 30 min 4°C Kim and Pfeiffer 1999 OSP Purified myelin 35-days-old mice TX-100 / CHAPS Brij 96V / TX-102 1% 30 min 4°C Taylor et al 2002 30-days-old rat brain TX-100 1% 30 min 4°C Kim and Pfeiffer 1999 35-days-old mice TX-100/CHAPS Brij 96V/TX-102 1% 30 min 4°C Taylor et al 2002 4-months-old mice: WT and MAL KO CHAPS na 30 min 4°C Schaeren-Wiemers et al 2004 Adult mouse brain CHAPS 20 mM 30 min 4°C 2-year-old mice TX-100 2% 30 min 4°C Saravanan et al 2004 Purified myelin Bovine brain E20 -E40 CHAPS 1.5% 30 min 4°C Debruin et al 2005 …”

“…Cell line Oli-neu (mouse) TX-100 2% 30 min 4°C Krämer et al 1997 4-months-old mice CHAPS na 30 min 4°C Schaeren-Wiemers et al 2004 Purified myelin Adult mouse brain TX-100 2% 30 min 4°C Krämer et al 1997Krämer et al , 1999 Mouse OLGs 5/8 DIV TX-100 2% 30 min 4°C Krämer et al 1997Krämer et al , 1999 Kim and Pfeiffer, 1999;Krämer et al, 2001] …”

Clustering and Activity Tuning of Kv1 Channels in Myelinated Hippocampal Axons

“…A recent study suggests that the expression of TAG-1 in myelin cells is sufficient to rescue the JXP complex and phenotypes of TAG-1 knock-out mice (24), questioning the function of axonal TAG-1. Furthermore, deleting other proteins with different functions in mice also disrupted precise Kv1 JXP clustering (25)(26)(27)(28)(29)(30), suggesting that proper functions of many proteins are required. Due to the lack of a system suitable for molecular studies, the mechanism that is both necessary and sufficient to cluster Kv1 channels in JXP regions remains unclear.…”