In ALS, is TDP-43 being produced to control herv-kC4?

I was just commenting on "Evidence for Fungal Infection in Cerebrospinal Fluid and Brain Tissue from Patients with Amyotrophic Lateral Sclerosis" and by the time I finished I had a question about TDP-43.

I believe that artificial deficiencies in complement control are playing a role in creating massive confusion about what is happening in ALS, and candida is a very good example.

What I have been studying in the research on ALS is from a complement perspective. Factor h is supposed to be pulling C3b off the spines of ALS patients and that isn't happening, so, what's happening to factor h? This is where I started looking. I lead me to the mass range of complement evasion strategies, and candida is huge in this department.

The other thing that I found about candida is that it is cleaved by galectin-3 without going through complement (Kohatsu et al), but it favour salmonella (Li et al) . Galectin-3 has been identified as cadidate biomarker for ALS (Zhou et al).

So, then you have studies on galectin-3 in ALS (Lerman et al), and I guess because galectin-3 appears to be increasing quite out of control, they did a gene knock out for galectin-3 and progression was faster.

I haven't found a specific reference for this, "Borrelia binds GAL-3 to induce Walerian degradation of myelin tissues, (creates artificial GAL-3 deficiency)." Dinglasan et al has many evasion strategies of borrelia but it did not specifically mention galectin-3. Binding factor H is a big problem with borrelia.

Candida has a lot of complement evasion strategies (Lou et al). It captures host complement regulators, such as Factor H, FHL-1, C4BP and plasminogen from human plasma to its surface. Creating artificial deficiencies in these complement components is a big problem in ALS. Factor H is needed to protect self cells and I believe C4 is a very critical player in ALS.

So then, cleaving candida with galectin-3 leads to potentially more salmonella problems and salmonella can also mess up complement. According to Ho et al, salmonella can also bind C4b and factor h, so more messing up these complement components. This same study mentions that E.coli can also evade complement with the same strategies. C4 is the second step to the complement cascade response.

Other pathogens can be messing up complement, Aspergillus also binds both factor H and C4b (Vogl et al), and B Steptococcus (Maruvada etal) and Streptococcus pyogenes (Haapasalo et al) both bind to factor H.

Aspergillus is probably huge in ALS. How do you get cluster data for ALS in an apartment building? (Melmed et al) My best educated guess is mold.

Back to how huge C4 is in ALS. Sekar et al have an excellent explanation and study on the different alleles of C4. Herv-k lives in C4 and is implicated in ALS (Li et al). According to Sekar et al, "First, RNA expression of C4A and C4B increased proportionally with copy number of C4A and C4B respectively (Fig. 3a, band Extended Data Fig. 4). These observations mirror earlier observations in human serum 24. Second, expression levels of C4A were two to three times greater than expression levels of C4B, even after controlling for relative copy number in each genome (Fig. 3c). Third, copy number of the C4–HERV sequence increased the ratio of C4A to C4B expression (P < 10 −7, P < 10 −2, P < 10 −3, respectively, in the three cohorts examined, by Spearman rank correlation)." So, a certain copy of C4 results in more herv-k and that copy is also associated with schizophrenia.

With messed up complement more C4 is needed to get the complement cascade going properly, but because of this mess, there is potentially way more herv-k.

Another interesting point, there is about 150 times the risk of ALS to Jewish pedigrees with schizophrenia in their family (Goodman et al).

And then it seems, TDP-43 suppresses retroviruses, for example HIV (Kuo et al). So then the question I have is about TDP-43, is it being produced to control herv-k?

It also seems that treatment with antivirals for HIV has been a beneficial treatment for HIV ALS patients (Smith et al).

References

Kohatsu, Luciana, et al. "Galectin-3 induces death of Candida species expressing specific β-1, 2-linked mannans." The Journal of Immunology 177.7 (2006): 4718-4726.

Li, Yubin, et al. "Galectin-3 is a negative regulator of lipopolysaccharide-mediated inflammation." The Journal of Immunology 181.4 (2008): 2781-2789.

Zhou, Jian-Ying, et al. "Galectin-3 is a candidate biomarker for amyotrophic lateral sclerosis: discovery by a proteomics approach." Journal of proteome research 9.10 (2010): 5133-5141.

Lerman, Bruce J., et al. "Deletion of galectin‐3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1 G93A mouse model of amyotrophic lateral sclerosis." Brain and behavior 2.5 (2012): 563-575.

Dinglasan, Rhoel R., and Marcelo Jacobs-Lorena. "Insight into a conserved lifestyle: protein-carbohydrate adhesion strategies of vector-borne pathogens." Infection and immunity 73.12 (2005): 7797-7807.

Luo, Shanshan, et al. "Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans." Molecular immunology 56.3 (2013): 161-169.

Ho, Derek K., et al. "Functional recruitment of human complement inhibitor C4B-binding protein to outer membrane protein Rck of Salmonella." PloS one 6.11 (2011): e27546.

Vogl, G., et al. "Immune evasion by acquisition of complement inhibitors: the mould Aspergillus binds both factor H and C4b binding protein." Molecular immunology 45.5 (2008): 1485-1493.

Maruvada, Ravi, Nemani V. Prasadarao, and C. E. Rubens. "Acquisition of factor H by a novel surface protein on group B Streptococcus promotes complement degradation." The FASEB Journal 23.11 (2009): 3967-3977.

Haapasalo, Karita, et al. "Acquisition of complement factor H is important for pathogenesis of Streptococcus pyogenes infections: evidence from bacterial in vitro survival and human genetic association." The Journal of Immunology 188.1 (2012): 426-435.

Melmed, Calvin, and Charles Krieger. "A cluster of amyotrophic lateral sclerosis." Archives of neurology 39.9 (1982): 595.

Sekar, Aswin, et al. "Schizophrenia risk from complex variation of complement component 4." Nature 530.7589 (2016): 177-183.

Li, Wenxue, et al. "Human endogenous retrovirus-K contributes to motor neuron disease." Science translational medicine 7.307 (2015): 307ra153-307ra153.

Goodman, Ann B. "Elevated risks for amyotrophic lateral sclerosis and blood disorders in Ashkenazi schizophrenic pedigrees suggest new candidate genes in schizophrenia." American journal of medical genetics 54.3 (1994): 271-278.

Kuo, Pan-Hsien, et al. "Structural insights into TDP-43 in nucleic-acid binding and domain interactions." Nucleic acids research 37.6 (2009): 1799-1808.

Smith, Bryan, et al. "Activation of HERV-K and response to antiretroviral therapy in patients with HIV infection and motor neuron disease (S37. 001)." Neurology 84.14 Supplement (2015): S37-001.

Tassabehji et al. 1994. Identification of a novel family of human endogenous retroviruses and characterization of one family member, HERV-K(C4), located in the complement C4 gene cluster. Nucleic Acids Res 22:5211–5217