title: Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction.
abstract: Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Whereas oligodendrocytes have been considered the primary neural cell type most affected, recent evidence indicates that axonal and neuronal degeneration also occurs in both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model reproducing many features of multiple sclerosis. The molecular mechanisms underlying neuronal deficits in multiple sclerosis and EAE remain elusive. To address this issue, we have analysed the expression of genes encoding proteins that play critical roles in ion homeostasis, exocytosis, mitochondrial function and impulse conduction in the Lewis rat lumbar spinal cord during the clinical course of acute EAE. Transcript and protein levels of plasma membrane Ca(2+) ATPase 2 (PMCA2), an essential ion pump expressed exclusively in grey matter and involved in Ca(2+) extrusion, synapsin IIa and syntaxin 1B, important regulators of vesicular exocytosis, were dramatically decreased coincident with the onset of clinical symptoms. In contrast, changes in the expression of several other ion pumps, vesicular proteins, mitochondrial enzymes and sodium channels occurred at more advanced disease stages. Moreover, exposure of spinal cord slice cultures to kainic acid significantly reduced PMCA2 mRNA levels. Taken together, our findings suggest that glutamate, which recently has been implicated in EAE pathogenesis, suppresses neuronal PMCA2 expression leading to Ca(2+) dyshomeostasis at initial clinical phases. Consequently, perturbations in Ca(2+) balance and neurotransmitter exocytosis may partially underlie aberrant neuronal function and communication at onset of symptoms. Altered mitochondrial function and impulse conduction may exacerbate neurological deficits at subsequent disease stages.
authors.affiliation: Department of Neuroscience, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nicot
authors.forename: Pillarisetty V
authors.initials: PV
authors.lastname: Ratnakar
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ron
authors.forename: Chiann-Chyi
authors.initials: CC
authors.lastname: Chen
authors.forename: Stella
authors.initials: S
authors.lastname: Elkabes
mesh_terms: D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins; D046508:Culture Techniques; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D053499:Plasma Membrane Calcium-Transporting ATPases; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D015222:Sodium Channels; D003576:Electron Transport Complex IV; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D007608:Kainic Acid; D002118:Calcium