Abstract
Profiling of gene expression changes in mice harbouring the neurodegenerative Wlds mutation shows a strong correlation between changes in cell cycle pathways and altered vulnerability of terminally differentiated neurons.
Highlights
Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons
The Wlds gene encodes a fusion protein that comprises the full length of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a nicotinamide adenine dinucleotide [NAD+] synthesizing enzyme), coupled by a unique 18-amino-acid sequence to the amino-terminal 70 amino acids of the ubiquitination enzyme ubiquitination factor E4B (Ube4b) [14]
To verify that the alterations in cell cycle gene expression were occurring as a direct result of the presence of Wlds, and to further confirm that RNA changes observed in Wlds mouse cerebellum led to corresponding changes in protein levels, we examined the effects of Wlds on cell cycle in human embryonic kidney (HEK293) cells after transfection with enhanced green fluorescent protein-tagged Wlds constructs [22]
Summary
Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons. The neuroprotective slow Wallerian degeneration (Wlds) mutation delays degeneration in axonal and synaptic compartments of neurons following a wide range of traumatic and disease-inducing stimuli, providing a powerful experimental tool with which to investigate modulation of neuronal vulnerability. The mechanisms through which Wlds confers neuroprotection remain unclear, a diverse range of downstream modifications, incorporating several genes/pathways, have been implicated These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube). Despite providing substantial protection for axons and synapses, cell bodies are not protected in Wlds mice [17,18,19]
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