Differential expression of molecular motors in the motor cortex of sporadic ALS

The molecular mechanisms underlying the selective neurodegeneration of motor neurons in amyotrophic lateral sclerosis (ALS) are inadequately understood. Recent breakthroughs have implicated impaired axonal transport, mediated by molecular motors, as a key element for disease onset and progression. The current work identifies the expression of 15 kinesin-like motors in healthy human motor cortex, including three novel isoforms. Our comprehensive quantitative mRNA analysis in control and sporadic ALS (SALS) motor cortex specimens detects SALS-specific down-regulation of KIFIB beta and novel KIF3A beta, two isoforms we show to be enriched in the brain, and also of SODl, a key enzyme linked to familial ALS. This is accompanied by a marked reduction of KIF3A beta protein levels. In the motor cortex KIF3A beta localizes in cholinergic neurons, including upper motor neurons. No mutations causing splicing defects or altering protein-coding sequences were identified in the genes of the three proteins. The present study implicates two motor proteins as possible candidates in SALS pathology. (c) 2007 Elsevier Inc. All rights reserved.