Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis

Abstract

The causative pathomechanism of sporadic amyotrophic lateral sclerosis (ALS) is not clearly understood. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons isolated from autopsied patients with sporadic ALS were examined. Gene expression was quantitatively assessed by real-time reverse transcription polymerase chain reaction and in situ hybridization. Spinal motor neurons showed a distinct gene expression profile from the whole spinal ventral horn. Three percent of genes examined were downregulated, and 1% were upregulated in motor neurons. Downregulated genes included those associated with cytoskeleton/axonal transport, transcription, and cell surface antigens/receptors, such as dynactin, microtubule-associated proteins, and early growth response 3 (EGR3). In contrast, cell death-associated genes were mostly upregulated. Promoters for cell death pathway, death receptor 5, cyclins A1 and C, and caspases-1, -3, and -9, were upregulated, whereas cell death inhibitors, acetyl-CoA transporter, and NF-kappaB were also upregulated. Moreover, neuroprotective neurotrophic factors such as ciliary neurotrophic factor (CNTF), Hepatocyte growth factor (HGF), and glial cell line-derived neurotrophic factor were upregulated. Inflammation-related genes, such as those belonging to the cytokine family, were not, however, significantly upregulated in either motor neurons or ventral horns. The motor neuron-specific gene expression profile in sporadic ALS can provide direct information on the genes leading to neurodegeneration and neuronal death and are helpful for developing new therapeutic strategies.

Mutant SOD1 and mitochondrial damage alter expression and splicing of genes controlling neuritogenesis in models of neurodegeneration

“…For example, we observed a progressive increase in the expression of Hgf during disease course. HGF, which has neurotrophic effects in the motor neurons and central nervous system, was found to be upregulated in motor neurons of sporadic ALS patients (Jiang, et al, 2005). In addition we found increased expression of Cxcr4 from pre-symptomatic to end-stage.…”

“…In G93A-Sod1 transgenic mice, a considerable inhibition of retrograde axonal transport was observed at a very early stage of disease before animals became symptomatic (Jiang, et al, 2005). We observed downregulation of several members of the kinesin family in both experimental paradigms.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…A gene expression profile analysis performed on laser microdissected degenerating motor neurons from sporadic ALS patients revealed the down-regulation of the cbp gene [120]. A comparison of HDAC expression revealed a reduction of HDAC 11 mRNA and increased HDAC 2 levels in postmortem ALS brain and spinal cord specimens [121].…”

Age‐specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro

“…disease (Luthi-Carter et al ., 2002;Sipione et al ., 2002), dentatorubralpallidoluysian atrophy (Luthi-Carter et al ., 2002), and amyotrophic lateral sclerosis (Jiang et al ., 2005) were also identified.…”