Up-regulation of genes involved in cellular stress and apoptosis in a rat model of hippocampal degeneration

Abstract

Changes in gene expression within the hippocampus induced by denervation after electrolytic fimbria-fornix lesion in rat were compared to morphological and biochemical alterations. Fimbria-fornix lesion results in degeneration of hippocampal cholinergic terminals as evidenced by a sustained (2 days to 1 month) decrease in cholineacetyltransferase (ChAT) activity (50%). These changes were accompanied by a decrease in growth associated protein 43 (GAP-43) immunoreactivity in all hippocampal layers 4 days after lesion followed by a subsequent increase and return to normal levels by 20 days postinjury. This increase in GAP-43 expression in the hippocampus between 7 to 20 days after lesion may reflect heterotypic sprouting. TUNEL-positive cells were revealed by in situ assay within the hippocampus at 10 days, but not at 3 days, after lesion. Two subtracted cDNA libraries from the dorsal hippocampus of control and injured rats (at 3 and 10 days postlesion) were constructed in order to search for new genes potentially implicated in degeneration/regeneration phenomena. We analysed 1,536 clones from each library by differential screening and found a total of 46 up-regulated genes. Among the 15 known genes, 6 coded for proteins involved in signal transduction pathways. The upregulation of growth arrest DNA damage induced gene (GADD153), brain-specific RING finger protein, JNK interacting protein (JIP-1), protein kinase A (PKA), and Na+K+ ATPase was studied by quantitative polymerase chain reaction (PCR). Two of these genes, GADD153 and JIP-1, have been previously shown to participate in cell modifications induced by stress and apoptosis.

Gene expression pathways induced by axotomy and decentralization of rat superior cervical ganglion neurons

“…This is a transcription factor that is overexpressed in hippocampal neurons just before the initiation of the apoptotic cascade that occurs when they are deprived of the cholinergic afferents (Anguelova et al ., 2000). In SCG, downregulation of this gene is consistent with the absence of deafferentation/axotomy‐induced neuronal death (Snider et al ., 2002).…”

AP-1 proteins in the adult brain: facts and fiction about effectors of neuroprotection and neurodegeneration

“…Apart from renal jip1 mRNA, the JIP1-3 proteins are highly expressed in the brain (Kim et al, 1999) with cytoplasmic and axonal-presynaptic distribution (Pellet et al, 2000), and complexes with MLK2 and activated JNK have been found along microtubules in ®broblasts . Expression of JIPs can be enhanced at a transcriptional level following ischemia (Hayashi et al, 2000), neuronal denervation (Anguelova et al, 2000) or inhibition of JNK (Levresse et al, 2000) with an immediate impact on JNK activation, since the overexpression of JIPs relative to JNKs blocks JNK functions (Ferrell, 2000). The JNK-associated protein 1 (JSAP1), which is synonymous to JIP-3 and displays a preference for JNK3 (Ito et al, 1999), antagonizes the activation of ERKs by inhibition of the Raf-1 mediated MEK1 phosphorylation (Kuboki et al, 2000).…”

Changes in Brain MicroRNAs Contribute to Cholinergic Stress Reactions

“…At the physiological level, cholinergic neurotransmission is altered under stress (Kaufer et al 1998; Soreq and Seidman 2001). These stress-induced changes are mostly attributed to the combinatorial regulation of many genes’ altered transcription levels (Anguelova et al 2000). However, the contribution of posttranscriptional regulation mechanisms to these stress-associated responses is increasingly acknowledged (Battaglia and Ogliari 2005; Gattoni et al 1996; Meshorer et al 2005).…”