Problems in Single Protein, Gemin3, May Underlie ALS Despite Its Diversity, Study Suggests

A single protein called Gemin3 may be the bridge linking the varied proteins known to underlie amyotrophic lateral sclerosis (ALS), suggesting a common pathway in this disease, a study using a fruit fly model showed. 

The discovery of this common pathway may pave the way to treatments that could be effective for many ALS patients, its researchers said. 

The study, “SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1,” was published in the journal Nature. 

Mutations in different genes, with varied roles in health, are implicated in the development of both familial and (the much more common) sporadic ALS, a motor neuron disease. These include the Chromosome 9 open reading frame 72 (C9orf72), Cu/Zn superoxide dismutase 1 (SOD1), transactive response DNA binding protein (TARDBP or TDP-43) and fused in sarcoma (FUS) genes.

“We have been perplexed by the seemingly diverse functions of genes linked to ALS. The lack of commonality complicates the process for developing treatments that are broadly beneficial,” the study’s lead author, Ruben J. Cauchi, PhD, a principal investigator at the University of Malta, said in a press release.

Another motor neuron disease, one of infancy and childhood known as spinal muscular atrophy (SMA), is caused by mutations in the survival motor neuron 1 (SMN1) gene that lead to little or no SMN protein being produced. SMN is part of a large multiprotein complex critical for the processing of RNA — the molecules that carry the genetic message from genes to make proteins.

ALS and SMA are considered separate diseases because of their differences in terms of genetics, disease onset, and the type of neurons affected. But recent studies report that proteins linked to ALS interact with SMN or other proteins in the SMN complex.

Both diseases are characterized by defects in RNA processing, and the depletion of proteins that form part of the SMN complex — known as Gemins (gem-associated proteins). They also can co-occur within families. 

A loss (deletion) or duplication of the SMN gene is also known to increase the risk of ALS.

Gemin3 (DDX20) is a protein in the SMN complex that plays a role in many cellular processes, including RNA metabolism. Cauchi and his research team wondered if Gemin3 may be associated with the proteins linked to ALS.

The researchers used fruit flies (Drosophila melanogaster) as a model organism, as over half of the genes that cause disease in humans are found in fruit flies. Their genes are also easy to manipulate, the flies reproduce quickly, and they are inexpensive to acquire — all points of research interest. 

Similar to SMN1 mutations, mutations leading to a loss of function for Gemin3 affects the viability of adult fruit flies and induces motor dysfunction. 

Researchers created a mutant version of the Gemin3 and expressed it (produced its protein), along with the ALS-linked TDP-43, whose protein at excessive levels led to problems for the flies with climbing and an inability to fly. Problems with the TPD-43 protein have been identified in around 5% of familial ALS, and fewer than 1% of sporadic ALS cases.

While a decrease in TDP-43 levels had no impact on motor deficits and fly survival with a mutant Gemin3 gene, increases in levels of its protein triggered the death of Gemin3 mutant flies at earlier life stages. Likewise, rising levels of TDP-43 killed flies at earlier ages, indicating a direct interaction between the proteins TDP-43 and Gemin3. 

An increase or decrease in the working of the FUS gene was also found to affect the motor abilities and viability of flies producing a problematic Gemin3 protein (because of mutations in its related gene), again demonstrating a connection between the Gemin3 and FUS proteins. 

While no link was found between C9orf72 and Gemin3, a loss of SOD1 function also caused motor deficits in flies with Gemin3 mutations.

Finally, in the Gemin3 mutant flies, increases in TDP-43 or FUS protein levels led to greater muscle atrophy (wasting) and poorer muscle–nerve communication.

The researchers speculate that these intersecting pathways all contribute to the health and optimal function of the neuromuscular system.

And they propose “Gemin3 as a candidate for modifying motor neuron degeneration,” as a “common [disease] pathway.”

“Our findings point to an overlap in disease-causing mechanisms underlying each different ALS-causing gene,” Cauchi added. “This can potentially unveil new targets for therapies that are effective in a wide range of ALS patients.”