NDR White Paper Issue 11: Mechanisms of common pathologies in ALS

Despite the initial cause, all cases of ALS, familial or sporadic, follow a final common pathogenesis. The ability for the body to resolve disease becomes overwhelmed and innate response pathways increase disease, rather than resolve disease. It is a conundrum that the information to effectively treat ALS patients require knowledge of the real time disease process. This conundrum may be a big factor in the failure of ALS drugs in clinical trials. Solving this conundrum will require identification of biomarkers to stratify patients.


RNA codes for regulatory proteins that can bind RNA. These RNA-binding proteins can be dysregulated and affect RNA metabolism. RNA itself, in some cases, can contribute to pathology through several pathways. A very important RNA-binding protein is TAR DNA-binding protein (TDP-43). Although TDP-43 is found in the nucleus of the cell, it was implicated in neurodegeneration when it was found in ubiquitin-positive cytoplasmic inclusions, which are a hallmark of sporadic ALS cases. Evidence shows that coding mutations in TARDBP cause disease in a rare number of dominantly inherited cases of fALS. These observations indicate TDP-43 is both a pathological hallmark of sALS and functionally related to some, but not all fALS pathogenesis.

 

Ongoing investigations by NDR Inc are evaluating metabolomic data from ALS cases. These cases will be evaluated by exposomics that evaluate 802 compounds including pesticides, flame retardants, plastics, and organic pollutants.

 

The forgoing indicates sequence dependent ALS risk factors could elicit disease. Because ALS is rare, most researchers believe there are other factors that trigger disease when genetic risk factors exist. These are age, infections, toxins, or environmental factors. There are so many new toxic chemicals in the environment since WWII it would be impossible to narrow down a causal association with ALS, unless there was an event that led to multiple cases in a short time. One of the most discussed environmental connections to neurological disease is the relationship between aluminum exposure and Alzheimer’s disease, Parkinson’s and ALS. The literature demonstrates negative impacts of aluminum on the nervous system across age span.


Intriguing possibilities in the etiology of ALS are enteroviruses, positive-stranded RNA viruses. The significance of linking a viral etiology to ALS is the possibility of using anti-viral therapies as options for treating ALS. The mechanism of enteroviral persistence in the CNS of infected individuals is due to the predilection of the virus to attack glial cells and neuronal progenitor cells. Human endogenous retrovirus are remnants of ancient retroviruses integrated into the human genome and normally inactive, but they can be reactivated under stress.

Studies detecting retroviral elements in ALS are controversial. The discrepant results between studies can be due to stage of disease, patient selection, experimental method selection, integrity of viral RNA, and sensitivity of the tests. A bystander mechanism has been proposed. The bystander mechanism is present after the virus is eliminated. In these cases, an active virus won’t be detected, and anti-viral treatments won’t work.


A significant theme in ALS is protein misfolding. Disease-related proteins encoded by ALS-causative genes form aggregates in the cellular processes that regulate RNA and protein quality control. The cross-talk between the signaling pathways that regulate the processes lead to pathological cascades mediated by accumulation of mutant RNA binding proteins.




The folding of a protein is key to its function and specificity in cell systems. Mutations in the aforementioned SOD1 proteins link to longevity is probably related to protein structure. Mutated proteins that don’t bind RNA can exert an increased (gain of function) or decreased (loss of function) function by changes dictated by its structure. For example, a misfolded SOD1 protein may increase binding of phosphokinases by exposing new phospho-reactive sites, this can be a gain of toxic function. There is some evidence that inhibiting mitogen activated protein kinases (MAPK) alleviate some aspects of ALS. The changes in the function of proteins can be regulatory or toxic. Identifying the dysregulated system in an individual is key to resolving disease.


The complicated nature of ALS prevent identification of the causal factors and even the stage of the disease process. It is possible to get hints at effective treatments by evaluating the many clinical trials that have been conducted in people, the literature available on PUBMed can be informative. Often clinical trials do not attain a successful level, but some patients do show a beneficial decline in progression of disease, just not enough to move the therapy along to patients suffering from disease. The ability to define sub-sets of patients that have participated in clinical trials using genetics, metabolomics, and biological responses could reveal what and when a treatment should be used in a specific patient. A meta-analysis of existing clinical trial data may be transformative to target appropriate enrollment into future clinical trials and is a worthy endeavor.


NDR White Paper Issue 11 Jan 2022
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