Abstract
A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements and the function of external sphincters, with corresponding preservation of motor neurons in the brainstem oculomotor nuclei, and of Onuf’s nucleus in the sacral spinal cord. Studying the differences in properties of neurons that are vulnerable and resistant to the disease process in ALS may provide insights into the mechanisms of neuronal degeneration, and identify targets for therapeutic manipulation. We used microarray analysis to determine the differences in gene expression between oculomotor and spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls. We compared these to transcriptional profiles of oculomotor nuclei and spinal cord from rat and mouse, obtained from the GEO omnibus database. We show that oculomotor neurons have a distinct transcriptional profile, with significant differential expression of 1,757 named genes (q < 0.001). Differentially expressed genes are enriched for the functional categories of synaptic transmission, ubiquitin-dependent proteolysis, mitochondrial function, transcriptional regulation, immune system functions, and the extracellular matrix. Marked differences are seen, across the three species, in genes with a function in synaptic transmission, including several glutamate and GABA receptor subunits. Using patch clamp recording in acute spinal and brainstem slices, we show that resistant oculomotor neurons show a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than vulnerable spinal motor neurons. The findings suggest that reduced susceptibility to excitotoxicity, mediated in part through enhanced GABAergic transmission, is an important determinant of the relative resistance of oculomotor neurons to degeneration in ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-1058-5) contains supplementary material, which is available to authorized users.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder, in which there is selective loss of motor neurons in the cerebral cortex, brainstem and spinal cord
We demonstrate the functional impact of altered expression of Gamma-aminobutyric acid (GABA) and glutamate receptors on whole-cell currents induced by agonists at GABA and glutamate receptors
A total of 1,521 unique named genes were upregulated in OM neurons, and 236 in lumbar spinal cord (LSC) motor neurons, at a significance level of q \ 0.001, which was the threshold used for downstream analysis (Table 2)
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder, in which there is selective loss of motor neurons in the cerebral cortex, brainstem and spinal cord. Mean survival from onset is 3 years. There is loss of lower motor neurons in the ventral horn of the spinal cord, with astrocytic gliosis, and the presence of ubiquitinated inclusions in surviving motor neurons. 5 % of ALS cases are familial, and 70 % of these have mutations in C9ORF72, SOD1, TDP43 or FUS. In the majority of ALS cases, the cause of motor neuron degeneration is unknown, a number of pathogenic processes, including excitotoxicity, oxidative stress, protein aggregation, mitochondrial dysfunction, dysregulation of the cytoskeleton and axonal transport, and inflammation are considered to play important roles [9]
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