Pathogenesis of SOD-1 related ALS reportedly found.

In a paper in Cell, Stem Cell this month, abstract below, the researchers say that they have found a plausible cause for ALS in persons with the mutant SOD1 gene. It seems that SOD1 modulates neurofilament composition, and that the mutant SOD1 enzyme causes one of the three protein subnits (MF-L, the smallest subunit of the proteins which make up the microscopic filament used to transport nourishment down the axon of the motor nerve cell) to be in such a short supply that the transport mechanism fails, eventually leading, it is supposed, to complete motor neuron failure.

This currently would only apply to persons with the rarer, hereditary form of ALS. The further question is whether in the more common forms of the disease that the neurofilament subunit misproportions will also be seen, or not.

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ABSTRACT

Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1

Evangelos Kiskinis, Jackson Sandoe, Luis A. Williams, Gabriella L. Boulting, Rob Moccia, Brian J. Wainger, Steve Han, Theodore Peng, Sebastian Thams, Shravani Mikkilineni, Cassidy Mellin, Florian T. Merkle, Brandi N. Davis-Dusenbery, Michael Ziller, Derek Oakley, Justin Ichida, Stefania Dicostanza, Nick Atwater, Morgan L. Maeder, Mathew J. Goodwin, James Nemesh, et al.

Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.

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