Dr. James P. Bennett, Jr., Director, Parkinson’s Research Center of Virginia Commonwealth University and inventor of Dexpramipexole, is also a dedicated researcher on behalf of ALS/MND. We hope this sharing of important insights and information today and future contributions from others will foster continuing dialogue and greater levels of collaboration and communication.
"When I lecture about neurodegenerative diseases, one of the slides I show early in my talk is a charcoal drawing of blind men feeling different parts of an elephant. This is to remind me and the audience that the characteristics of the “elephant” we feel depend on what part we touch. This analogy is very relevant to complex diseases like ALS, the “elephant” where many investigators examine different parts.
A comprehensive understanding of ALS and related diseases requires recognition by all that the life and death of cells are very complex events, they depend on many processes (and possibly neighboring cells) for survival, and that seemingly disparate findings can tell us something about this complexity. One group’s findings in ALS do not necessarily validate or invalidate those of another. Assuming that we all do our best to present the truth as we find it, each new set of findings are like brush strokes in a painting; in isolation their meaning may not be clear, but grouped together, we might be able integrate them into a coherent image.
In trying to understand and develop therapies for complex neurodegenerative diseases like ALS, we all strive to find the coherent image that allows us to propose interventions. Even if ALS develops from a common genesis event and progresses along similar molecular pathways in all sufferers, both of these assumptions being very unlikely if not already disproven, none should expect a single “magic bullet” that would alter theoffending molecule, receptor or pathway. Rather, it seems that our collective obligation is to become increasingly sophisticated systems biologists to discern how “big picture” events are being altered. This approach applies to disease origins, progressions and selective cell vulnerabilities.
In that context, three recent publications offer us different but not competing visions of what ALS is.
First, Nardo, et al used gene expression microarrays of vulnerable motor neurons captured from spinal cords of two highly related transgenic mouse strains that both expressed a common familial human ALS SOD1 mutation (“G93A”). They analyzed gene expression patterns in motor neurons from two different mouse backgrounds, 129Sv that rapidly progress and die younger than C57, even though both mice expressed the same mutant human SOD1 at about the same level. The differences were striking, as if two completely different diseases were being studied. 129Sv-SOD1 mice extensively lost (“downregulated”) expression of multiple genes involved in functions of mitochondria and protein quality control. On the other hand, C57-SOD1 mice had completely different expression patterns. They increased expression of survival genes, those that are protective and those that can positively modulate inflammatory responses.
Kang, et al used a similar transgenic SOD1 mouse model and reported on a different “part of the elephant”, the failure of a particular kind of supporting cell (oligodendroglia) to help keep motor neurons alive. In their SOD1 mice, “oligos” that normally form insulating myelin (white matter) around nerve cell processes became dysfunctional and their precursors died prematurely, leaving demyelinated patches in the ALS mice. Human ALS spinal cords showed similar findings. Further, by selectively suppressing expression of mutant SOD1 expression in oligodendroglial precursors, the transgenic mice developed ALS symptoms later and lived on average 3 months longer.
Finally, Grad, et al showed how normal (“wild-type”, w.t.) SOD1 protein can form aggregated clumps in rodent motor neurons and can spread to adjacent motor neurons in culture. This spread, reminiscent of prions (infectious proteins), occurred by at least two mechanisms- uptake of protein clumps from dead cells by living ones through “macropinocytosis”, a type of engulfment and internalization, or through “exosomes”, vesicles secreted by many different cell types that can contain various cell components. This passage of clumped SOD1 aggregates occurred to other cell types, including spinal cord cells in culture, and was shown to be dependent on intact w.t. SOD1. Because aggregated SOD1 protein is a significant component of human ALS spinal cords, this “prion-like” transmission might explain spread of ALS pathology to neighboring cells.
What are we to make of these seemingly disparate findings; is there a coherent image of ALS to be found? I propose that from these recent papers we learn that ALS:
Is a process that can alter the transcriptome (the total expression of thousands of genes in a cell) in radically different ways, depending on disease aggressiveness;
Is a disease whose primary cell vulnerability (motor neurons) is intimately tied to the health of neighboring cells;
Is a pathological progression that could arise from spread of prion-like protein aggregates of an important w.t. enzyme implicated extensively in familial/genetic forms of the disease.
These are all parts of ALS complexity. None by itself provides the complete image we seek, and most importantly, there are many additional parts to feel. It is also difficult to predict whether interruption or change of any single process will alter disease progression. While we seek a more comprehensive image, we must also strive to find ways to change the abnormalities we find and test them, if safe, in those with ALS."