Induction of the immediate early gene c-jun in human spinal cord in amyotrophic lateral sclerosis with concomitant loss of NMDA receptor NR-1 and glycine transporter mRNA.
The aetiology of the sporadic form of amyotrophic lateral sclerosis (ALS) is poorly understood although abnormalities in glutamate and glycine transport have been implicated which both could contribute to a neurodegenerative process mediated through the N-methyl-D-aspartate (NMDA) receptor. In this study we have used in situ hybridization to investigate whether any changes in the expression of NMDA receptors, the glycine transporter or glutamate-mediated injury responses are detectable in ALS. Two immediate early genes were investigated as markers of neuronal injury responses, c-jun and zif-268, both constitutively expressed in the spinal cord. Levels of c-jun mRNA were most abundant in intermediate grey and layer IX of the ventral horn containing motor neurones. This pattern was markedly changed in ALS with large increases (2-3 fold) in c-jun mRNA occurring in dorsal and ventral horn. The marked increase in c-jun mRNA was also substantiated by slot blot analysis of tissue homogenates of spinal cord and a parallel induction of zif-268 mRNA was also seen. NMDA receptor NR-1 mRNA was widely distributed in control spinal cord with the highest concentrations occurring in layers IX, X, intermediate grey and dorsal horn. The ALS cases showed a selective decrease in the level of NR-1 mRNA in the ventral region (50%) whilst no significant decrease was detected in the dorsal region. Quantitation of tissue homogenates with dorsal and ventral regions combined also yielded a significant decrease of 40% which supports the analysis from in situ hybridization densitometry.(ABSTRACT TRUNCATED AT 250 WORDS)
Virgo
L
L
Department of Biochemistry, Charing Cross and Westminster Medical School, London, UK.
de Belleroche
J
J
D000328:Adult; D000368:Aged; D026921:Amino Acid Transport Systems, Neutral; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary; D005260:Female; D017781:Genes, Immediate-Early / Q000235:genetics; D005998:Glycine / Q000235:genetics / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
D026921:Amino Acid Transport Systems, Neutral; D002352:Carrier Proteins; D018076:DNA, Complementary; D050487:Glycine Plasma Membrane Transport Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine