How TDP-43 trigger inflammation in Amyotrophic lateral sclerosis

Significance 

Motor neuron disease (MND) is a progressive condition that occurs when certain nerve cells degenerate and die. There are two types of motor neuron cells. The upper motor neuron begins in the brain and ends in the spinal cord. The lower motor neuron starts in the spinal cord and ends in the muscles. Now researchers from Melbourne are working to develop a potential treatment to slow the progression of MND, by taking the “sting” out of it, literally. By blocking an immune sensor called STING, the researchers were able to prevent inflammation from MND patient cells in mouse models. Their findings may open a new door of drug development for those with MND and neurodegenerative disorders.

Their findings are published in Cell and led by Professor Seth Masters at Walter and Eliza Hall Institute with colleagues from the University of Melbourne.

Most people suffering from MND have an accumulation of a protein called TDP-43 within cells of the central nervous system. At least 60 mutations in the TARDBP gene have been linked to amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most mutations change amino acids in the TDP-43. Changes to the TDP-43 protein cause the protein to misfold and form protein clumps, which have been found in nerve cells that control motor neurons in some people with ALS.

The researchers investigated how the disease-causing inflammation is triggered in MND. This unexpectedly identified that an immune sensor called STING is activated downstream of TDP-43. The research team had already studied the role of STING in other inflammatory diseases and are now working out how to block it.

The team then used new inhibitors to block different components of this inflammatory pathway. Using cells from patients with MND, the researchers showed that blocking STING dramatically prevented inflammation and kept the cells alive longer.

Stimulator of interferon genes (STING) is a signaling molecule associated with the endoplasmic reticulum and is essential for controlling the transcription of numerous host defense genes, including type I interferons (IFNs) and pro-inflammatory cytokines.

The researchers are now looking forward to validating a biomarker of the pathway earlier in the disease progression. Once this neuroinflammatory biomarker is validated, It will be better understood which patients will benefit the most from treatments targeting the pathway.

Preclinical studies suggested that although the anti-inflammatory drugs that inhibit STING did not prevent disease onset, they did slow the degenerative progression of disease. The researchers are hopeful that their treatment could lead to more understanding and new treatments and extend life expectancy and dramatically improve the quality of life for people diagnosed with MND.

How TDP-43 trigger inflammation in Amyotrophic lateral sclerosis - Medicine Innovates

About the author

Associate Professor Seth Masters

Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia

His lab focus is on inflammasomes and autoinflammatory disease. In particular inflammation generated by the innate immune system. This can happen in many different contexts, including during infection, when cells die, or when genetic mutations activate innate immune pathways causing autoinflammatory disease. Inflammation contributes to the development of many chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, amyotrophic lateral sclerosis (ALS) and type 2 diabetes.

His research interest is in innate immune receptors known as Nod-like receptors (NLRs). Many of these have the capacity to form intracellular protein complexes called inflammasomes. These biological structures process the pro-inflammatory cytokines IL-1b and IL-18 into their mature forms. His research has identified substances that activate the inflammasome, and mechanisms by which this inflammation causes disease.

Activation of the inflammasome also triggers an inflammatory form of cell death known as pyroptosis. This programmed form of cell death is a way by which an infected cell can prevent the spread of a microorganism, but it can also contribute to inflammatory pathology during disease. We are researching the triggers and effectors for this new form of cell death.

Reference

Chien-Hsiung Yu, Sophia Davidson, Cassandra R. Harapas, Kate McArthur, Peter J. Crouch, Seth L. Masters. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Cell, Published: October 07, 2020 DOI: https://doi.org/10.1016/j.cell.2020.09.020

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