Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS

Amyotrophic lateral sclerosis (ALS) is characterised by motor neuron death and accumulation of ubiquitinated protein inclusions. Motor neurons are large-calibre and long distance projection excitatory cells with unusually high energetic, synthetic and transport demands required for maintenance and survival. These neurons are therefore likely to be uniquely susceptible to intracellular transport abnormalities in cell bodies and distal axons. Here, we review increasing evidence that motor neuron vulnerability in ALS may be conferred by defects in intracellular trafficking pathways specialised for these cells. Firstly, many of the genes implicated in familial forms of ALS encode molecular machinery or enzymes directly mediating intracellular transport. Secondly, these ALS gene products and additional constituents of trafficking pathways form core components of pathology in familial and sporadic disease. Lastly, defective membrane, vesicle, protein and mRNA transport features prominently and early in motor neuron degeneration in ALS models. We provide a systematic summary of ALS-linked proteins including ALS2, CHMP2B, FIG4, FUS, OPTN, p150Glued, SOD1, TDP-43, VAPB and VCP with respect to their localisation, function and dysfunction in intracellular trafficking pathways, such as anterograde and retrograde axonal transport, endoplasmic-Golgi, endosome-lysosome and nuclear transport. The role of molecular motor-linked proteins such as kinesin, dynein and neurofilaments in motor neurodegeneration will also be addressed. We propose that intracellular membrane trafficking defects affecting key neuronal functions, such as neurotransmission, extracellular signalling and synaptic activity, may be an early determinant of motor neuron loss and common denominator of potentially many ALS-linked proteins.36 page(s