ALS Briefs: Protein Clumps, Cell-to-Cell Spread and More

This roundup of recent MDA-supported amyotrophic lateral sclerosis (ALS) research news and reviews includes:

Formation of TDP43 protein clumps

Protein clumps (aggregates) containing TDP43 protein are found in the motor neurons in nearly all ALS, but it's unknown whether they help drive the ALS disease process, are the product of a cellular defense mechanism to sequester malformed and potentially toxic proteins, or have some other function.

Now, findings from an MDA-supported study have shed light on what governs the formation of these aggregates in ALS, frontotemporal dementia (FTD) and other neuromuscular disorders.

Using human- and mouse-cell models, Robert H. Baloh at Cedars-Sinai Medical Center in Los Angeles, and colleagues, found that TDP43 protein aggregate formation in the cell nucleus is regulated by "chaperone" proteins and a section of the TDP43 protein called the C-terminal prion domain.

The researchers say their data suggest that under conditions of cell stress, TDP43 aggregation may be triggered in the cell by the C-terminal prion domain, which "senses" that internal conditions in the cell are out of balance, and unfolds or misfolds in response. Sufficient levels of chaperone proteins help to keep the number of misfolded proteins to a minimum, but in cases where availability of these helper proteins is low, misfolded TDP43 proteins are left to form aggregates.

The team published its findings online Aug. 19, 2013, in Human Molecular Genetics. MDA supported Baloh and Conrad C. Weihl, both at Cedars-Sinai, for their work on this project. For more, read ALS: Misfolded TDP43 Appears to Spread.

Cell-to-cell spread of neurodegenerative disease

An Aug. 22, 2013, Washington University (St. Louis) press release describes findings from an MDA-supported study that show one way in which corrupted, disease-causing proteins spread in the brain, transferring between cells and ultimately causing nerve cell death throughout the nervous system.

The research team, led by Marc I. Diamond at Washington University School of Medicine in St. Louis, identified heparan sulfate proteoglycans (HSPGs) — a specific type of receptor — as a key element in the process, and suggested that blocking it may prevent the cell-to-cell spread of corrupted proteins linked to Alzheimer’s disease, Parkinson’s disease and other brain-damaging disorders including, possibly, ALS.

The team published its findings online July 29, 2013, in Proceedings of the National Academy of Sciences. MDA supported Diamond for his work on this project. For more about cell-to-cell spread of ALS, see Why Does ALS Spread?

Diagnostic method detects free radical activity

Free radicals (toxic chemicals that are byproducts of energy production inside cells) associated with oxidative stress are thought to play a role in ALS.

Understanding the extent and timing of events triggered by free radicals in animal models is important because these are major determinants of disease evolution and prognosis.

Now, researchers in an MDA-supported study have shown that noninvasive monitoring of free radicals in rodent neurological disease models is possible through the combination of two technologies: molecular magnetic resonance imaging (mMRI) and immune-spin trapping (IST). Kenneth Hensley, at the University of Toledo Health Sciences Campus in Toledo, Ohio, and colleagues, used the method to detect free radical activity in the spinal cords of SOD1 mice, a model for ALS. Hensley received MDA support for his work on this project. The team published its findings online May 28, 2013, in Free Radical Biology and Medicine.

The immune system in ALS

Evidence shows that early in the course of ALS, the immune system works to rescue and repair damaged motor neurons, but as the disease progresses, a shift occurs and the immune response becomes harmful.

In a review published online July 25, 2013, in Journal of Neuroimmune Pharmacology, Weihua Zhao, David R. Beers and Stanley H. Appel, all at Methodist Neurological Institute in Houston, discuss the alterations and distinct characteristics of immune system cells at the different stages of ALS.

Better understanding of immune system behavior, they say, will inform therapy development for the disease. Appel, a longtime MDA grantee, received MDA support for his work on this project. He serves as director of the MDA/ALS Center at Methodist and chairman of MDA's Medical Advisory Committee.

RAN translation

Well-established rules in molecular biology describe the role genes play in the construction of proteins, what proteins a cell synthesizes, how proteins work and the consequences of gene mutations.

But for a group of neurological diseases caused by the abnormal expansion of short segments of DNA (repeat expansion mutations), an unanticipated, non-standard protein construction process called repeat associated non-ATG (RAN) translation results in the generation of a series of "repeat proteins" — unexpectedly manufactured ("translated") proteins that reflect the abnormalities caused by the expansion mutations.

"This finding opens the door to new paradigms in disease mechanisms and cell biology," note John D. Cleary and Laura P.W. Ranum, both at the University of Florida in Gainesville, in a review highlighting what is currently known about RAN translation and recent progress toward understanding its contribution to disease.

To date, RAN proteins have been reported in spinocerebellar ataxia type 8 (SCA8); type 1 (MMD1, or DM1) and type 2 (MMD2, or DM2) myotonic dystrophy; fragile X tremor ataxia syndrome (FXTAS); and C9ORF72-associated ALS and frontotemporal dementia (FTD).

Cleary and Ranum published their review online Aug. 4, 2013, in Human Molecular Genetics. See Repeat-Associated Non-ATG (RAN) Translation in Neurological Disease. MDA supported Ranum for her work on this project.

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