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I'll try to make a list of potentially interesting clues that seem to correlate with ALS or could explain some aspects of the disease.

1. MMP-9 enzyme:

In a follow-up experiment, the researchers confirmed that the product of MMP-9, MMP-9 protein, is present in ALS-vulnerable motor neurons, but not in ALS-resistant ones. Further, the researchers found that MMP-9 can be detected not just in lumbar 5 neurons, but also in other types of motor neurons affected by ALS. "It was a perfect correlation." said Dr. Henderson. "In other words, having MMP-9 is an absolute predictor that a motor neuron will die if the disease strikes, at least in mice."

There is an ongoing thread on MMP-9 at the ALSTDI forum: (requires registration on the said forum).


2.  Misfolded wild-type SOD1 (and the potential for its prion-like spreading)

While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a “toxic conformation” that is similar to familial ALS-linked SOD1 variants.

Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWt-SOD1 propagation has been established, misfolding of HuWt-SOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates.


This thesis, p. 39, mentions the possibility of misfolded SOD1 binding to the cytosol-side of VDAC1, consequently blocking transport of pyruvate and ADP into the mitochondrion. This could in turn prevent oxidative phosphorylation of pyruvate and cause a shift in the cell metabolism towards less efficient fermentation to lactic acid. Open question: How does AKG enter mitochondria? Could it avoid the blockade caused by misfolded SOD1 on VDAC1, and could this explain why some followers of the Deanna protocol claim to benefit from consuming AKG?

The reference cited is:
Israelson A, Arbel N, Da Cruz S, Ilieva H, Yamanaka K, Shoshan-Barmatz V and 
Cleveland DW. (2010) Misfolded Mutant SOD1 Directly Inhibits VDAC1 
Conductance in a Mouse Model of Inherited ALS. Neuron; 67: 575-87.


3. Failures in axonal transport

Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.

Before now, scientists have understood that with ALS, so-called tangles - misshapen protein - along the nerve's paths block the route along the nerve fibers, which eventually results in the nerve fiber malfunctioning and dying.

The team's recent discovery, however, has to do with the source of these tangles, which lies in a shortage of one of three proteins in the neurofilament.

Zhang explains that the neurofilament plays both a structural and a functional role:

"Like the studs, joists and rafters of a house, the neurofilament is the backbone of the cell, but it's constantly changing. These proteins need to be shipped from the cell body, where they are produced, to the most distant part, and then be shipped back for recycling.

If the proteins cannot form correctly and be transported easily, they form tangles that cause a cascade of problems."


He says their discovery is that the origin of ALS is "misregulation of one step in the production of the neurofilament."

Additionally, he notes that similar tangles crop up with Alzheimer's and Parkinson's diseases: "We got really excited at the idea that when you study ALS, you may be looking at the root of many neurodegenerative disorders."