Abstract
ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post-mortem ALS human donors affected by the sporadic form of the disease (which comprises ~90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons
Our study includes ventral horns of the lumbar spinal cord from six human donors affected by sporadic ALS and five age, sex and ethnicity matched controls (Table 1)
The intensity of SNAP25 and STX1A signal was normalized on the size of motor neuron cell body that we found to be reduced by almost 50% in ALS patients (Fig. 9B)
Summary
ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. Amyotrophic lateral sclerosis (ALS) is a fatal and devastating neurodegenerative disorder that causes the progressive death of upper and lower motor neurons[1]. Much effort has been done in elucidating molecular factors underlying the onset and progression of the disorder, the causes of ALS remain unknown[2]. Microarray-based transcriptome studies have revealed multiple perturbations of motor neuron function in both forms of ALS3, 4, consistent with the hypothesis that various cellular events, including mitochondrial dysfunction, enhanced apoptosis, glutamate-mediated excitotoxicity, free radical injury, protein misfolding, Bari, Italy. Correspondence and requests for materials should be addressed to G.P.
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