Molecular Pathways in ALS

Identifying and understanding genes that play a major role in ALS to develop potential treatments

Full Project Name:Systematic Analysis of Molecular Pathways Implicated in Amyotrophic Lateral SclerosisPrincipal Investigator:Allison Ebert, PhD, Cell Biology, Neurobiology and AnatomyCo-Investigator:Brian A. Link, PhD, Cell Biology, Neurobiology and Anatomy; Kenneth M. Scaglione, PhD, BiochemistryAward Amount:$200,000

Award Date

July2015

Project Duration:24 months

Project Description Narrative:

Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor nerve cell disease, causing muscle weakness, paralysis, and death most often within two to five years of diagnosis. Currently, no treatments exist that go beyond relieving symptoms to resist the underlying causes of the disease.

Only about 5-10% percent of cases of ALS are caused by inherited mutation. Advances have been made in determining the genes involves in this hereditary form, although little is yet understood about how these mutated genes work in concert to cause ALS.

Through this award, scientists will study both the functions of the inherited mutant genes and the genetic underpinnings of non-hereditary ALS cases. The generation of new knowledge about the similarities and differences of hereditary and non-hereditary ALS may lead the design of new approaches to treating ALS.

Outcomes & Lessons Learned:

Identified important molecular targets that, through further research, could lead to new therapies for ALS
Found that motor neurons derived from ALS patient samples have altered expression of aggregation prone proteins and aberrant expression of the small heat shock proteins and chaperones designed to keep these proteins from aggregating. Protein aggregation is a common feature of a number of neurodegenerative diseases. However, studies have not been able to definitively determine how protein aggregates impact neuronal function because no effective therapies have been designed to eliminate the aggregates. Using the dictyostelium model (sometimes referred to as slime mold), the research team identified a novel gene that prevents protein aggregation. With the discovery of a novel gene, the research team has the opportunity to explore its use in ALS models as well as in other neurogenerative disease systems, which could have a significant impact on the basic biological understanding of what protein aggregates do in the neurons and if this gene will be an effective therapeutic agent. Additionally, previous studies examining protein aggregation and heat shock proteins in ALS have relied on over-expression systems; data from this research exhibits protein burden and heat shock protein misexpression in endogenous conditions, which should provide more clinical relevance
Leveraged more than $3.2 million in additional funding for related research
Published one paper and conducted 10 presentations