Evidence for Nuclear Pore Dysfunction in ALS

This article looks at a few recent papers providing initial evidence for nuclear pore dysfunction to be a important contributing cause of at least some forms of Amyotrophic lateral sclerosis (ALS). This is perhaps of general interest to those of us following aging research, as nuclear pore proteins in at least some long-lived neurons seem to last as long as we do; they are either never replaced over the length of a human life span, or replaced only very slowly. Nuclear pore structures are responsible for the transport of molecules across the nuclear membrane in cells, and there is speculation that accumulated molecular damage to these pores might contribute to aspects of brain aging. From this viewpoint, ALS might be a condition that occurs due to one specific form of age-related cellular damage progressing at a much faster pace than usual, a pattern that exists in a number of age-related diseases only suffered by a portion of the population.

Three studies, analyzing in different ways the leading ALS gene, came to what is being called a remarkably similar conclusion: the most common form of ALS may be caused by clogged pores in brain cell nuclear membranes. One of the studies identified two drug options that eradicated the pore clogging. All identified druggable targets. "These are the first studies to implicate altered nucleo-cytosolic transport as a mechanism of pathology in ALS. The findings are presently limited to the significant subset of ALS cases caused by the C9 mutation that is found in 40 percent of inherited ALS and frontotemporal dementia (FTD)." Two of the papers also showed that TDP-43, a protein known as key in ALS, appears mislocalized by the C9 mutation, and the authors show that this mislocalization can be rescued.

"Discovery of TDP-43 mislocalization - from nucleus into cytoplasm - as a predominant occurrence in ALS and FTD has provided a major change of perspective on these diseases. The complexity of underlying processes that can cause TDP-43 proteinopathy has been highlighted by the discovery of C9 in ground-breaking studies. However, none connected C9 with the major pathology in patients: TDP-43 proteinopathy. These new studies bring this connection closer. They show RNA from C9 mutation can disrupt nuclear pore shuttling by binding to proteins driving this process. The bigger question is whether nuclear import defects contribute to the pathogenesis of sporadic as well as inherited familial ALS. This is being looked at by multiple labs. If the answer is 'yes,' one can imagine modulators of nuclear import might emerge as a major therapeutic avenue in ALS. No doubt such drugs will be given a hard look."

Link: http://www.biosciencetechnology.com/articles/2015/09/three-remarkable-studies-say-clogged-pores-may-cause-als-drug-targets-idd

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