The ALS Association

Ice Bucket Challenge Progress

New genes and new pathways reveal potential new targets for treatment

December 21, 2012

Researchers at the Amyotrophic Lateral Sclerosis (ALS) Motor Neuron Disease (MND) International Symposium met for three long and intense days in December 2012 to discuss the newest research on all aspects of ALS.  Below is the summary of one of these important topics: 

New Understanding of Protein Recycling in ALS

     New genes and new pathways reveal potential new targets for treatment

Proteins are the workhorses of all types of cellular processes and make up much of the bulk of each cell.  When proteins wear out, they must be broken down and recycled, so that they do not clog up the cell and interfere with other proteins.  In people with ALS, defective proteins accumulate in the motor neurons, leading researchers to believe there is a problem with the protein recycling systems that may cause or worsen disease.

Worn out or defective proteins are broken down within the cell by two different processes or pathways.  These are known as the ubiquitin-proteasome pathway and the autophagy pathway. The first is typically used for individual proteins, while the second is used for protein complexes and large subcellular units called organelles.  Recently, researchers have begun to focus intently on both processes for clues to understanding their role in ALS.

“Autophagy is now emerging as a highly selective quality control mechanism,” said Anne Simonsen, Ph.D., of the Institute of Basic Medical Sciences in Oslo, Norway.  Her group has found that an autophagy-linked protein called ALFY (autophagy-linked FYVE protein) plays a key role in aiding the removal of protein aggregates, including those seen in neurodegenerative diseases such as ALS and Huntington’s disease.  Several ALS-linked genes appear to take part in this clearance pathway, and Dr. Simonsen’s work is aimed to understanding it further, ultimately to find targets for enhancing it as a therapeutic strategy in ALS.

Another key protein in the autophagy system is called Beclin 1.  Eichi Tokuda, Ph.D., of Umea University in Sweden explained that in a mouse model of ALS, loss of Beclin 1 accelerates the disease process, suggesting that this protein’s function normally helps slow the disease.  It likely does that by promoting autophagic clearance of aggregates of the mutant SOD1 protein.  This result leads to two conclusions: 1) it supports the rationale for therapies that reduce mutant SOD1 and 2) suggests that boosting autophagy may be one such strategy.

A recently discovered ALS gene, ubiquilin 2, may also take part in the pathway.  Faisal Fecto, Ph.D., of Northwestern University in Chicago, has shown that ALS-causing mutations in the gene lead to the accumulation of ineffective components of the pathway, suggesting that interruption of the process may contribute to the disease, and again strengthening the case that boosting autophagy may be therapeutic.

More News from the Symposium, visit:

Why are some Motor Neurons More Vulnerable than Others?  Understanding why ocular motor neurons are spared may lead to protective strategies for all motor neurons

The Roles of Nonneuronal Cells in ALS: Astrocytes and immune cells are shaping up as key players in the ALS disease process

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