Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays

Abstract

In order to obtain insight into the aetiology and pathogenesis of amyotrophic lateral sclerosis (ALS), high-density gene discovery arrays (GDA human version 1.2) containing 18 400 non-redundant EST cDNAs pooled from different tissue libraries have been used to monitor gene expression in lumbar spinal cord from ALS cases compared with controls. Quantitative filter analysis revealed differential expression of cDNAs normalized to internal standards. These candidates have been further investigated and their expression in spinal cord characterized in a panel of ALS and control subjects. Significant differential expression was obtained for 14 genes, 13 being elevated (up to six-fold) and one decreased (by 80%) in ALS. Amongst those elevated in ALS were thioredoxin and glial fibrilary acid protein, which have already been shown to be up-regulated in ALS, thus supporting the reliability of this approach. The other differentially regulated transcripts confirmed in the expression studies represent potential candidates in ALS pathogenesis being involved in antioxidant systems, neuroinflammation, the regulation of motor neurone function, lipid metabolism, protease inhibition and protection against apoptosis. The use of the GDA system has greatly facilitated the screening and retrieval of sequence information and has generated useful information on the cascade of molecular events occurring in ALS and potentially may highlight new candidates playing a role in the aetiology and progression of this disease.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

“…1 In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. 2 Other evidence can be found about increased levels of GRN mRNA in several inflammatory neurodegenerative disorders associated with microglial activation, such as amyotrophic lateral sclerosis 3 and virally induced central nervous system inflammation. 4 A contribution of GRN variability has also been previously shown in sporadic FTLD, 5,6 although another study did not confirm these data.…”

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

“…Pathologically, the TAR DNA binding protein 43 (TDP-43) was found as a major constituent of polyubiquitinated neuronal inclusions [Neumann et al, 2006] in both FTLDU and ALS patients [Neumann et al, 2006;Arai et al, 2006]. Moreover, a 400% increase of GRN expression has been observed in the spinal cord of patients with ALS [Malaspina et al, 2001] and Creutzfeldt-Jakob disease (CJD) [Baker and Manuelidis, 2003], most likely as a result of the activation of microglia. In AD and Lewy-body related diseases, TDP-43 immunoreactivity was also observed [Amador-Ortiz et al, 2007;Nakashima-Yasuda et al, 2007;Higashi et al, 2007].…”

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

“…In the central nervous system PRGN is highly expressed in neurons of the cerebral cortex, particularly in the granule cells of the hippocampus, and in the Purkinje cells of the cerebellum [Daniel et al, 2000]. In other neurodegenerative diseases upregulation of PGRN was observed in microglia of Creutzfeldt-Jacob patients and in spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS) [MIM# 105400] [Baker and Manuelidis, 2003;Malaspina et al, 2001]. …”