Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection

Abstract

The main pathological features of multiple sclerosis, demyelination and axonal transection, are considered to cause reversible and irreversible neurological deficits, respectively. This study aimed to separately analyze the effects of these pathological hallmarks on neuronal gene expression in experimental paradigms. The pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or a complete pathway transection (axonal transection) in rats. Transcriptional changes in the pontocerebellar neurons were investigated with microarrays at days 4, 10 and 37 post-intervention, which was confirmed by immunohistochemistry on protein level. A common as well as unique set of injury-response genes was identified. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. The expression of Atf3 in a patient with Marburg's variant of multiple sclerosis was also detected, also confirming the activation of the Atf3 pathway in a human disease sample. It was concluded that this experimental approach may be useful for the identification of pathways that could be targeted for remyelinative or neuroprotective drug development.

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

“…Transcriptional changes often underlie differences in cellular function, and gene expression profiling has been undertaken in experimental chemical demyelinating lesions (Lovas et al, 2010) as well as in MS to examine neuronal gene changes (Dutta et al, 2007Schirmer et al, 2019). took advantage of the variable degree of demyelination within individual MS hippocampi to assess the influence of demyelination on gene expression.…”

Activating transcription factor 3, an early cellular adaptive responder in ischemia/reperfusion-induced injury

“…Furthermore, a study reported that ATF3 was upregulated in the inflamed spinal cord of animals with constriction injury of the sciatic nerve [ 35 ] and in the pontine nuclei following demyelination of the pontocerebellar tract. In a patient with Marburg's variant of multiple sclerosis, ATF3 was found in neurons within the pontine nuclei and neocortex [ 36 ]. A caveat is that the extent of axonal injury in such cases of demyelination remains unknown.…”

Activating Transcription Factor 3 and the Nervous System

“…Pontocerebellar neurons show a prolonged (weeks) upregulation of ATF3 after axotomy (Lovas et al, 2010). The same applies to dopaminergic neurons in the substantia nigra pars compacta (Song et al, 2008), and olivocerebellar neurons following axotomy within the cerebellum (our unpublished observations).…”

“…In a patient with Marburg’s variant of multiple sclerosis ATF3 was found in neurons within the pontine nuclei and neocortex (Lovas et al, 2010). A caveat is that the extent of axonal injury in such cases of demyelination remains unknown.…”