Understanding the big hitters in Lou Gehrig’s disease: loading our knowledge bases to discover a home run for treatment

BioTechniques News
Aisha Al-Janabi

In recent weeks several research papers have been published all providing valuable new insight into the roles and functions of key proteins and pathways involved in amyotrophic lateral sclerosis (ALS).  

Three strikes for ALS

ALS, commonly referred to as Lou Gehrig’s disease after the former baseball pro who is thought to have suffered from the condition, is a common and fatal neuromuscular disorder that currently has no cure. Approximately 10% of ALS cases are caused by inherited genetic factors; however, whilst many risk factors correlated with ALS onset have been observed, the remaining percentage of cases do not have a clearly defined cause.  

Current treatments and diagnostics for ALS are limited by our underlying knowledge of the disease and a lack of identified ALS biomarkers and therapeutic targets. To improve this situation, a far greater understanding of ALS pathogenesis is required. 

A new therapeutic target steps up to the plate

Increased and continued inflammation is a common occurrence in the pathogenesis of neurological diseases including Alzheimer’s and Parkinson’s. Arachidonic acid is a pivotal fatty acid in the immune system’s inflammatory response, which has been linked to damage of neural tissue in these diseases, with high levels also observed in ALS. 

Gabsang Lee of Johns Hopkins University School of Medicine (MD, USA) recently led a team of researchers to discover that lipid metabolism pathway dysregulation may be responsible for the increased inflammatory response seen in ALS. As a result, they have identified a key catalytic step in this pathway which may serve as a potential target for ALS treatments [1,2].  

Lee explained that the study was inspired by the fact that ocular neurons maintain control of eye movements in people with ALS whilst muscle control is lost in spinal neurons. Lee set out to determine if there were any genetic differences between the neurons in ALS that explain this difference.   

By performing a multiomic analysis of stem-cell lines derived from a person with ALS, Lee’s team saw that these cells exhibited elevated levels of activity in genes that control lipid metabolism. Upon further investigation, researchers discovered that the concentrations and types of lipids present in spinal neurons of people with ALS varied significantly from those observed in ocular neurons. Furthermore, in those with ALS arachidonic acid was observed at 2.5 times the levels observed in people without the condition. 

Investigators administered the anti-inflammatory caffeic acid to drosophila and mouse models, aiming to lessen the impact of the arachidonic acid pathway and alleviate ALS symptoms. In drosophila models they observed improvements to the flies’ abilities to move and climb, whilst they also survived for longer. In the mouse models of ALS, a 20%–25% increase in grip strength and a 2 to 3 week increase in longevity was observed in the group administered with caffeic acid. 

The study performed by Lee’s team exemplifies the potential of targeting arachidonic acid levels in therapy for those with ALS. Nevertheless, Lee noted that further research is still to be undertaken to answer unknown factors “We don’t know yet why ocular and spinal neurons differ in lipid metabolism or what percentage of ALS patients have alterations in the arachidonic acid pathway”. 

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A brand new ballgame for Tau protein

In other neurodegenerative diseases including Alzheimer’s and Parkinson’s the Tau protein is observed to become hyperphosphorylated and be implicated in neurofibrillary degeneration in brain tissue. This form of Tau can aggregate forming neurofibrillary tangles and dissociating from microtubules in nerve cells [3,4].  

Two studies led by Ghazaleh Sadri-Vakili’s at the Massachusetts General Hospital (MA, USA) have focused on increasing our understanding of the Tau protein in ALS patients. 

The first study builds on the understanding that mitochondrial dysfunction has previously been implicated as a key stage in the progression of ALS. Similarities observed in Alzheimer’s have indicated that these changes can be attributed to the Tau protein. As Tau becomes hyperphosphorylated in Alzheimer’s, it facilitates interactions with other cellular proteins, namely dynamin-related protein 1 (DRP1) an enzyme involved in mitochondrial fission. By enabling mitochondrial fission, hyperphosphorylated Tau leads to an increase in reactive oxygen species and consequentially, oxidative stress. 

In this study, Sadri-Vakili examined post-mortem brain tissue from people who had suffered from ALS to assess if phosphorylated Tau protein was present and interacting with DRP1 in a similar way in ALS as Alzheimer’s.  

From their assessment, the research team found that in the brain tissue pTau-S396 is present and surprisingly aggregated in the motor cortex in all ALS subtypes. Utilizing ALS synaptosome treatment pTau-S396 induced oxidative stress and mitochondrial fission. DRP1 protein was demonstrated to be localized in a similar pattern to pTau-S396. The evidence suggests that ALS exhibits the same pathological stage as Alzheimer’s with the pTau-S396 and DRP1 interaction. 

After determining this stage occurred in ALS, Sadri-Vakili’s group administered QC-01-175 which degrades Tau protein and witnessed a reversal of these pathological symptoms. 

“We demonstrated for the first time that targeting Tau with a new class of small molecules that selectively degrade it can reverse the ALS-induced changes in mitochondria’s shape and function, highlighting Tau as a potential therapeutic target” explained Sadri-Vakili.  

Having identified this aberrant aggregation of pTau-S396 in the motor cortex, Sadri-Vakili continued to explore Tau, explaining that while the protein has been implicated in Alzheimer’s he wanted to determine, “…whether it plays a role in ALS pathogenesis as it can form aggregates and lead to cellular dysfunction in a number of neurodegenerative disorders.” 

The team discovered a genetic mutation of C9orf72 in some people with ALS that was associated with increased levels of Tau protein and the phosphorylated form pTau-S396 in post-mortem motor cortex tissue [5,6]. A version of Tau phosphorylated at a different residue, T181, showed decreased levels in all ALS motor cortex tissue samples, regardless of C9orf72 mutation 

Cerebrospinal fluid (CSF) samples from people with ALS were also analyzed to examine the ratio of pTau-T181 compared to total Tau protein. The T181 residue is contained within the proline-rich region and assists with Tau protein binding to microtubules and the decrease in pTau-T181 levels in ALS may contribute to the disease pathogenesis. The CSF levels of various forms of Tau protein have been all shown to vary differently in previous research in ALS as well as other neurodegenerative diseases. 

In their analysis Sadri-Vakili’s team discovered an increase in total Tau levels in people with a bulbar-onset subset of ALS whilst the CSF Tau-T181:Tau ratio decreased in all ALS cases. ALS disease progression was also found to be relative to the levels of the different Tau proteins. Higher total Tau levels indicated a faster disease progression, whilst decreases in CSF pTau-T181:Tau ratio related to slower progression, suggesting that the CSF Tau levels and ratio could make effective ALS biomarkers 

Additionally, the study highlighted 36 heterozygous variants of the MAPT gene, 15 of which were unique to ALS cases. The MAPT variants identified that are likely to contribute to ALS pathogenesis are all located adjacent to key phosphorylation sites T181 and S396. 

“We also identified new genetic mutations in the Tau gene that are specific to ALS and may have functional consequences that may exacerbate disease onset or progression” commented Sadri-Vakili. 

“It ain’t over till it’s over!”

ALS continues to be a debilitating condition without a current cure, but the research field is one base at a time giving us hope. By uncovering details of the metabolic pathway in those with ALS, new targets for treatment have been identified. Additionally, as Tau proteins continue to be studied the greater the understanding we have of ALS pathogenesis and the potential therapies for its reversal.   

Here’s hoping these three studies can count as three strikes for ALS! 

The post Understanding the big hitters in Lou Gehrig’s disease: loading our knowledge bases to discover a home run for treatment appeared first on BioTechniques.

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