Abstract
BackgroundMutations of the superoxide dismutase 1 (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS), an invariably fatal neurological condition involving cortico-spinal degeneration. Mechanical injury can also determine spinal cord degeneration and act as a risk factor for the development of ALS.ResultsWe have performed a comparative ontological analysis of the gene expression profiles of thoracic cord samples from rats carrying the G93A SOD1 gene mutation and from wild-type littermates subjected to mechanical compression of the spinal cord. Common molecular responses and gene expression changes unique to each experimental paradigm were evaluated against the functional development of each animal model. Gene Ontology categories crucial to protein folding, extracellular matrix and axonal formation underwent early activation in both experimental paradigms, but decreased significantly in the spinal cord from animals recovering from injury after 7 days and from the G93A SOD1 mutant rats at end-stage disease. Functional improvement after compression coincided with a massive up-regulation of growth-promoting gene categories including factors involved in angiogenesis and transcription, overcoming the more transitory surge of pro-apoptotic components and cell-cycle genes. The cord from G93A SOD1 mutants showed persistent over-expression of apoptotic and stress molecules with fewer neurorestorative signals, while functional deterioration was ongoing.Conclusionthis study illustrates how cytoskeletal protein metabolism is central to trauma and genetically-induced spinal cord degeneration and elucidates the main molecular events accompanying functional recovery or decline in two different animal models of spinal cord degeneration.
Highlights
Mutations of the superoxide dismutase 1 (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS), an invariably fatal neurological condition involving cortico-spinal degeneration
This study aims at advancing our understanding of spinal cord degeneration in two major areas: a) the identification of those molecular changes induced by mechanical trauma that may set the course of irreversible degeneration as seen in ALS, b) the main driving forces behind functional decline and recovery in geneticallyinduced and traumatic spinal cord degeneration
We have identified a dramatic down-regulation of this Gene Ontology (GO) category at 30 minute from spinal cord compression (SCC) coinciding with profound functional decline, followed by a 7-days significant over-expression of this gene category, while the animal model is in functional recovery
Summary
Mutations of the superoxide dismutase 1 (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS), an invariably fatal neurological condition involving cortico-spinal degeneration. Mechanical injury can determine spinal cord degeneration and act as a risk factor for the development of ALS. Spinal cord degeneration in humans resulting from a mechanical injury or developing in the context of a neurodegenerative disorder causes a variable degree of neurological disability. Clinical heterogeneity has been described in those 20% of familial ALS cases linked to mutations of the superoxide dismutase 1 (SOD1) gene, a genetic defect that exhibits a toxic gain of function that adversely affects motor neurons [2,3,4]. Recent epidemiological observations strengthen the case for the search for molecular mechanism of spinal cord tissue degeneration that may be activated by different pathological determinants. Cervical trauma has been singled out as one of the main risk factors for the development of ALS and this deadly neurological disorder seems to be seven times more prevalent in a large cohort of professional footballers in Italy [5]
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