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New ALS Risk Gene Suggests Role for Apoptosis

NEW YORK – Variants in an apoptosis-linked gene appear to increase the risk of developing amyotrophic lateral sclerosis, a new study has found.

ALS is a progressive, fatal neurodegenerative disease. While between 5 percent and 10 percent of cases are familial, most are sporadic, though genetic variants are still thought to contribute to disease risk.

By sequencing the exomes of 87 people with sporadic ALS, researchers from the University of Utah searched for genetic variants that might play a causal role in the disease and homed in on rare variants in the TP73 gene. As they reported in the journal Neurology on Wednesday, they sifted through data from nearly 2,900 further individuals with sporadic ALS to identify additional rare variants in TP73. These variants affect TP73 protein function, they showed, and knocking the gene out in a zebrafish model led to the impaired development of nerve cells, similar to what is seen in ALS.

"Much remains unknown about the genetics and processes that lead to the development of ALS," senior author Lynn Jorde, a professor of human genetics at the University of Utah, said in a statement. "Our study has identified a new genetic risk factor for sporadic ALS, rare mutations in the gene TP73."

He and his colleagues analyzed the exomes of 87 sporadic ALS patients from the University of Utah and 324 control individuals from the Simons Simplex Collection for genes with an excess amount of deleterious SNVs in ALS patients. A combined analysis using the VAAST and Phevor2 tools ranked two known ALS risk genes — MAPT and SOD1 — among the top 10 genes, but only TP73 was highly ranked by both approaches.

By expanding their analysis to include 2,940 additional ALS patients from the Utah Heritage 1K Project and the ALSdb cohort, the researchers identified 24 different, rare coding variants in TP73.

TP73 encodes p73, a member of the p53 gene family that has two main isoforms: TA-p73 and ΔN-p73. While TA-p73 induces expression of gene targets, ΔN-p73 inhibits the function of TA-p73 and p53. ΔN-p73, though, is the most common isoform in the brain where it promotes neuronal survival by preventing apoptosis.

In a series of functional analyses, the researchers tested how four of the variants they identified would affect ΔN-p73. Three variants led to significantly larger myotubes in a myoblast assay, reflecting dysfunctional apoptosis. Further, in a mouse neuroblastoma line, all four variants led to a decline in the ability of ΔN-p73 to bind to p53 and altered its ability to respond to apoptosis, possibly making motor neurons more vulnerable to apoptosis when stressed.

Additionally, CRISPR knockouts of the gene in zebrafish led to a reduction in the number of spinal motor neurons, suggesting that deleterious TP73 mutations could affect spinal motor neuron development and lead to motor neuron disease. The researchers further traced this reduction in motor neurons to increased apoptosis in the CRISPR knockouts.

In all, the findings suggested that apoptosis in motor neurons could be a key part of ALS pathology and contribute to disease risk, but that it could also help identify new treatment approaches.

"Together, our results strongly suggest that mutations in the gene TP73 increase the risk of ALS," Jorde said. "Our research indicates that cell death linked to these mutations may be a factor in the development of ALS. This discovery provides a new target for researchers working to develop therapies to slow or even stop the progression of ALS."