The Archetypes of Familial ALS Research

incursion into the dense field of amyotrophic lateral sclerosis (ALS) research has
revealed how limited our current knowledge is and how polarized some studies
are. For this and other reasons, navigating the literature is more complicated
than I expected at the beginning of the semester. Patterns emerged, though, and
each non-landmark research paper could be grouped into one of a few themes; the
landmark papers typically linked two or more of these themes, hence why they were
high-impact in the field. Here I will discuss these themes and the major scientific
advances that define contemporary and premodern ALS research.

First a note about terminology. ALS can be thought of
as a group of dozens, maybe hundreds of diseases with sufficiently similar
phenotypes at the tissue level (motor neuron death in the pyramidal tracts and other
areas) to call them the same condition. Many proteins are involved in the ALS
pathway, and malfunction in any of them can disrupt the pathway and cause the
same underlying problem of protein aggregates in neurons, just to different
extents and possibly involving different proteins composing the aggregates. Thus,
there are many genetic and nongenetic risk factors for ALS. About 10% of ALS
patients have familial ALS (FALS or ALS1), and most patients have sporadic ALS,
which is any of the other diseases that display ALS symptoms (ALS2, ALS3, ALS4,
etc.). Because of this similarity in different diseases, I am focusing in on
the most studied gene/protein, the Cu/Zu superoxide dismutase (SOD1,
15-20% of ALS1 patients), but researching treatment for all ALS cases because what
little effective treatment exists is usually effective for a range of patients
or was not studied on a specific gene or other risk factor. Organizing the
content this way will also help with smooth transitioning of my project research
into separate pages for the final project. Thus, for the purposes of this disease
project, “ALS” refers to all genetic and sporadic ALS diseases, “ALS1” refers to
only the ALS cases with predisposed genetic risk, and “FALS” refers to ALS1
with mutations in the SOD1 gene.

The first theme in ALS research is genomics. In 1993,
120 years after ALS was first described, SOD1 became the first gene to be
linked to ALS1. This was the beginning of a wave of genetic studies linking
mutations in many genes to ALS1. Since ALS1 is a disease of misfolded proteins
and usually only appears later in life, most (but not all) mutations that cause
ALS1 are dominant and many different mutations in the same gene can have the
same effect. Since ALS1 is so varied, many studies on ALS1 are simply
identifying new genes or mutations in the ALS pathway. There isn’t much unity or
building off other studies in this area of research; this is what I mean by polarized
research. However, genomics studies have allowed for more controlled studies in
other ALS research themes.

SOD1 FALS research focuses on the theme of the ALS metabolic pathway. It is characterized by the complex biochemical and biomolecular interactions that happen in diseased neurons. This theme is necessarily more integrated than genomics because metabolic activities overlap. All the mutations in SOD1 result in various disruptions, including elevated ROS concentrations, misfolded proteins that can form plaques and inhibit the proteasome, and mitochondrial malfunction. There is a persistent sub-theme of a prion-like mechanism; the literature isn’t as consistent here, with a few studies so far each mentioning it as a speculation or supporting the idea but with not enough evidence alone to justify the idea. From what I can tell, misfolded SOD1 proteins form insoluble plaques which can denature other proteins, forming more plaques and killing the neuron. No study I found said if or how these pseudo-prions are transferred from cell to cell, but presumably it would be via the synapse. A prion-like mechanism would explain why many genes and nongenetic factors cause ALS symptoms, since the plaques can form from healthy proteins as well, then progress from there.

The two smaller themes are treatment of ALS and tissue-level phenotypes. As mentioned earlier, the similar symptoms of all ALS mean treatment is also similar across patients. Adding to this generality is the general ineffectiveness of ALS treatment. To date no cure has been found for ALS, only ways to reduce the mental and physical toll on patients. The first ALS drug, riluzole, was developed in 1999 and was a long-awaited breakthrough, extending lifespan by an average of three months from diagnosis; minor advances have been made since then. ALS1 research progresses more quickly now with the beginning of genomics studies in 1993 and the creation of the first transgenic mouse model in 1994. From these, research has consistently found that presynaptic neurons (axons) and the pyramidal tract of the spinal cord are most affected, but which other neurons and glial cells are affected is tough to parse. This is not helped by how unspecific some older studies are about the underlying cause(s) of ALS in the patients they studied.

Grouping the literature could be done in many valid ways. I’m inclined to primarily categorize studies as either treatment or biochemistry and either pre- or post-genomics. Since the linkage of ALS1 with SOD1 and the mouse model occurred so close historically, it’s useful to identify if studies were done after the context of genomics and using the mouse model or not. Using this approach will integrate the content from my literature review and mastery assignment. No literature review is perfect, but clearly no disease is either. I will find a balance between the themes in ALS research and produce pages that are hopefully informative for laypeople.

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