ALS, SMA Share a Biochemical Pathway

New evidence links the motor neuron diseases ALS (amyotrophic lateral sclerosis) and spinal muscular atrophy (SMA), an international team of scientists has reported. The researchers say the findings could lead to the identification of therapeutic targets common to both disorders.

ALS and SMA both are diseases in which muscle-controlling nerve cells called motor neurons are lost. Mutated fused in sarcoma (FUS) proteins are responsible for a subset of familial and sporadic ALS, while a deficiency of functional SMN (survival of motor neuron) protein is the underlying cause of SMA.

The new data focus on biological structures called Gemini of coiled bodies, or “Gems,” which are believed to play a role in the processing of genetic instructions for generation of messenger RNA (an important chemical step in cellular protein production). Gems appear to be a common link in a shared biochemical pathway between ALS and SMA through interactions with FUS, SMN and another ALS-associated protein, tar DNA binding protein 43 (TDP43).

The findings support a growing body of evidence that defects in RNA processing play a significant role in motor neuron disease.

Loss of Gems occurs in both ALS, SMA

SMN protein normally is located inside Gems, within the cell nucleus. Under normal conditions, FUS and TDP43 also are properly located in the nucleus.

The investigators uncovered a set of interactions linking Gems and the ALS- and SMA-associated proteins: 

• FUS interacts directly with SMN.
• Gems, which are known to be lost in SMA, also are “dramatically reduced” in human cells containing ALS-causing FUS or TDP43 mutations; a similar finding was made previously in mice with ALS-causing SOD1 mutations.
• Functional, properly located FUS, TDP43 and SMN all are required for Gems formation.

The researchers, led by Robin Reed at Harvard Medical School in Boston, suggest that TDP43 function is necessary for the proper function of FUS, which in turn is necessary for assembling SMN into Gems.

They note that the loss of Gems in ALS potentially could be a biological marker, or biomarker, for the disease. If confirmed, it potentially could be used as a diagnostic tool to help determine whether someone who is presenting symptoms has ALS, or to identify FUS- and TDP43-associated subtypes of the disease.

In addition, the newly discovered common pathway could yield therapeutic targets common to both ALS and SMA.

The team published its findings online Sept. 27, 2012, in Cell Reports. Read the full report at no cost: FUS-SMN Protein Interactions Link the Motor Neuron Diseases ALS and SMA.

ALS and SMA: More connections?

To learn more about possible connections between ALS and SMA, read:

• ALS and SMA: Less EPHA4 Means More Motor Neurons Survive— an article describing how decreased activity of the EPHA4 receptor leads to extended life span in animal models of ALS and SMA, and in people with ALS, MDA/ALS Newsmagazine online, Sept. 3, 2012

• Mutant Superoxide Dismutase 1 (SOD1), a Cause of Amyotrophic Lateral Sclerosis, Disrupts the Recruitment of SMN, the Spinal Muscular Atrophy Protein to Nuclear Cajal Bodies— study results showing that mutant SOD1 protein, which is a cause of familial ALS, alters the location of SMN and prevents the formation of Gems, Neurology, May 11, 2012

• SMA Gene Associated with Sporadic ALS— an article that discusses study findings that show extra copies of the SMN1 gene (the gene that is deleted or mutated in SMA) correlate with a higher risk of sporadic ALS, MDA/ALS Newsmagazine online, Feb. 10, 2012

• More Can Be Less: SMN1 Gene Duplications Are Associated with Sporadic ALS— an editorial about the mechanism by which SMN1 duplications might cause susceptibility to ALS, Neurology, Feb. 8, 2012

• ALS/SMA – Miller— a description of MDA grantee Michael Miller's search for fundamental molecular mechanisms responsible for motor neuron death in both ALS and SMA, MDA Grants at a Glance, Winter 2011

• SMN1 Gene, but Not SMN2, is a Risk Factor for Sporadic ALS— a report of study results showing that abnormal SMN1 gene copy numbers are a genetic risk factor in sporadic ALS, Neurology, Aug. 23, 2006

• A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis— a research paper describing findings that link SMA and some subtypes of ALS through a single mutation in the VAPB gene, American Journal of Human Genetics, Sept. 15, 2004