New Insight into Neurodegenerative Diseases Through Transport Proteins

A new study by Professor Steven P. Gross, Developmental and Cell Biology, in collaboration with the Vallee lab at Columbia University, has discovered how a specific protein in cells changes the function of a motor protein, which may ultimately give insight into neurodegenerative diseases.

Microscopic transport of cargoes in different sub-cellular compartments is particularly important for extended cells such as neurons. Additionally, altered or impaired transport underlies a number of neurodegenerative diseases including Lou Gehrig’s disease (ALS), Huntington’s disease, and Alzheimer’s disease. Much of the transport is driven by a molecular motor protein called dynein, which is itself regulated by a protein called dynactin. While studies have repeatedly established the importance of dynactin, (impairing it dramatically inhibits transport, and a naturally occurring mutation leads to familial motor neuron disease), exactly how it controlled dynein function was unclear.

By examining single molecules of the molecular motor protein (dynein) transporting artificial cargoes, functioning either alone or with the protein dynactin, Professor Gross and colleagues discovered that dynactin can do two things. First, it can help position the two ‘feet’ of the dynein molecule relative to each other, so that the dynein walks better, without stumbling or falling off its track, resulting in improved directional transport. Second it can turn off dynein altogether, preventing it from interfering with transport along the track in the opposite direction.

Professor Gross and colleagues surmised that by preventing a tug-of-war between opposite motors propelling cells, the dynactin plays a critical role in avoiding the “traffic jams” that can result in impaired neuronal function. Each of these two functions is controlled by a different part of the dynactin molecule, so by controlling which part of dynactin interacts with dynein, overall dynein-mediated transport can be dramatically changed. Long-term, this new mechanistic understanding of cellular transport and its regulation should make possible the design of targeted therapeutic approaches to combat neurodegeneration.

The study appeared in Nature Cell Biology.

 

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