Antiviral Immune Response may trigger the FUS Proteinopathy form of ALS

- Posted by

Amyotrophic lateral sclerosis caused by mutations in the FUS gene is characterized by cytoplasmic FUS aggregates (FUS proteinopathy). Shelkovnikova et al. find that the antiviral immune response promotes FUS protein accumulation and its coalescence into persistent cytoplasmic assemblies. Viral infection can serve as a trigger of FUS proteinopathy in ALS.

enter image description here

Mutations in the FUS gene cause familial amyotrophic lateral sclerosis (ALS-FUS). In ALS-FUS, FUS-positive inclusions are detected in the cytoplasm of neurons and glia, a condition known as FUS proteinopathy. Mutant FUS incorporates into stress granules (SGs) and can spontaneously form cytoplasmic RNA granules in cultured cells.

However, it is unclear what can trigger the persistence of mutant FUS assemblies and lead to inclusion formation. Although FUS readily aggregates in the test tube, this is not the case in vivo, and available rodent models expressing mutant FUS do not develop FUS aggregates in the CNS. This is a very different behavior from mutated proteins like SOD1, C9orf72 or TDP-43. While those last three proteins can aggregate, the reason why they aggregate are different for each of them but are related to instability in their shape. FUS proteinopathy is different.

Epidemiological and clinical evidence for a connection between viral infection and ALS has been accumulating for decades (Celeste and Miller, 2018; Ravits, 2005; Vandenberghe et al., 2010). For example, it is known that individuals with a history of poliomyelitis have a higher risk of developing motor neuron disease later in life (Martyn et al., 1988). Similarly, patients infected with HIV or human T cell leukemia virus 1 develop neurological disorders resembling clinical features of ALS (Alfa- had and Nath, 2013). Indeed one of the multiple biological roles of TDP-43 (which is the cause of most ALS cases) is to mitigate HIV infections. Importantly, multiple viruses are able to induce SG assembly (McCormick and Khaperskyy, 2017; White and Lloyd, 2012).

In the current study, Tatyana A. Shelkovnikova and her colleagues show that the exposure to foreign double-stranded RNA (dsRNA), typical for some viral infections, is a potent inducer of persistent FUS-enriched assemblies in the cytoplasm of cells expressing either exogenous or endogenous mutant FUS. Furthermore, they show that type I interferon (IFN), the central component of antiviral signaling, promotes accumulation of FUS protein. They propose that the antiviral immune response, with its profound effect on FUS levels and distribution, can serve as a trigger of FUS proteinopathy in ALS-FUS.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Please, help us continue to provide valuable information: