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Fundamental ALS Pathology Discovered

Summary: Researchers have identified a genetic mutation associated with both ALS and frontotemporal dementia.

Source: St. Jude Children’s Research Hospital.

Identifying the basic cellular malfunction underlying amyotrophic lateral sclerosis and a form of dementia opens the pathway to developing treatments to prevent the disease by preserving neurons.

A team led by scientists at St. Jude Children’s Research Hospital and Mayo Clinic has identified a basic biological mechanism that kills neurons in amyotrophic lateral sclerosis (ALS) and in a related genetic disorder, frontotemporal dementia (FTD), found in some ALS patients. ALS is popularly known as Lou Gehrig disease.

The researchers were led by J. Paul Taylor, M.D., Ph.D., chair of the St. Jude Cell and Molecular Biology Department and a Howard Hughes Medical Institute investigator; and Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Florida. The findings appear today in the journal Neuron.

The disease-causing mutation identified is the first of its kind, Taylor said. Unlike in other genetic diseases, the mutation does not cripple an enzyme in a biological regulatory pathway. Rather, the mutation produces an abnormal version of a protein involved in a process called phase separation in cells.

Phase separation is a mechanism by which proteins assemble into organized assemblies, called membrane-less organelles, necessary for orderly cell functions. The researchers found that the ALS/FTD mutation produces an abnormal version of a protein called TIA1 that is a building block of such organelles. As a result, in ALS, the proteins accumulate and kill neurons that control muscles. In FTD, the accumulation kills neurons in the brain. The researchers noted that abnormal phase separation may also underlie Alzheimer’s disease.

There is currently no effective treatment for ALS/FTD. However, the researchers believe their finding offers a promising pathway for developing treatments to restore neurons’ ability to disassemble the organelles when their cellular purpose has ended.

The TIA1 mutation was discovered when the scientists analyzed the genomes of a family affected with ALS/FTD. Tracing the effect of the mutation on TIA1 structure, the researchers found that it altered the properties of a highly mobile “tail” of the protein. This tail region governs the protein’s ability to aggregate with other TIA1 proteins. Taylor and his colleagues previously identified such unstructured protein regions, called prion-like domains, as the building blocks of cellular assemblies and as hotspots for disease-causing mutations.

In further studies, the researchers found that TIA1 mutations occurred frequently in ALS patients. The scientists also found that people carrying the mutation had the disease. When the investigators analyzed brain tissue from deceased ALS patients with the mutations, the scientists detected a buildup of TIA1-containing organelles called stress granules in the neurons. Such granules form when the cell experiences such stresses as heat, chemical exposure and aging. To survive, the cell sequesters in the granules’ genetic material that codes for cell proteins not necessary for survival-critical processes.

The granules also contained a protein called TDP-43, another building block of stress granules, whose abnormality has been implicated in causing ALS. In test tube studies and experiments with cells, the researchers found that the TIA1 mutation causes the protein to become more “sticky,” delaying the normal disassembly of stress granules, trapping TDP-43.

“This paper provides the first ‘smoking gun,’ showing that the disease-causing mutation changes the phase transition behavior of proteins,” Taylor said. “And the change in the phase transition behavior changes the biology of the cell.”

More broadly, he said, “These findings are part of an emerging theme that there is a whole spectrum of diseases that includes ALS, and some forms of dementia and myopathy, that are caused by disturbance in the behavior of these structures that perturbs cellular organization.”

Image shows a dna strand.

In further studies, the researchers found that TIA1 mutations occurred frequently in ALS patients. NeuroscienceNews.com image is in the public domain.

The findings offer a highly promising pathway to the first effective treatments for ALS/FTD, Taylor said. Current drugs, which are only minimally effective, seek to improve the function of already damaged neurons. However, the new findings suggest the possibility of treatments that would prevent neuronal damage by restoring the healthy balance of phase separation in the cells of people with ALS/FTD mutations.

“We know that these material properties are under tight regulation, so perhaps we don’t have to target the disease-causing mutation itself,” Taylor said. “Perhaps we can restore balance by targeting any of a large number of regulatory molecules in the cell. There are already therapeutic approaches in laboratory testing that seek to do just that.”

In further studies, Taylor and his colleagues will seek to understand the basic process of phase transition. They will also map the regulatory machinery for stress granules, to seek potential therapeutic targets. He also noted that the same basic pathology of phase transition may also underlie other neurodegenerative diseases, including Alzheimer’s disease, and he is aiding researchers in applying the same research approach as in ALS/FTD to Alzheimer’s.

About this neuroscience research article

The paper’s joint first authors are Ian Mackenzie of Vancouver Coastal Health and the University of British Colombia; Alexandra Nicholson of Mayo Clinic Jacksonville; and Mohona Sarkar of St. Jude. Other St. Jude co-authors were Jamshid Temirov, Hong Joo Kim and Tanja Mittag. Co-authors were also from Vancouver Coastal Health and the University of British Colombia, Mayo Clinics, Simon Fraser University, University of Texas, Sunnybrook Health Sciences Centre, Northwestern University, University of Toronto, University of Western Ontario, Drexel University, Thomas Jefferson University and the University of Pittsburgh.

Funding: The research was funded in part by Mayo Clinic for Individualized Medicine; the Arizona Alzheimer’s Consortium; CREATE, the Canadian Institutes for Health Research; the National Institutes of Health (R35NS097974, R35NS076471, R35NS097273, P50AG016574, P50NS072187, P01NS084974, U01AG006576, U54NS092091, P30AG019610, R01AG031581, R01NS072248,R01NS075764); and ALSAC, the fundraising and awareness organization of St. Jude.

Source: Erin Seidler – St. Jude Children’s Research Hospital
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics” by Ian R. Mackenzie, Alexandra M. Nicholson, Mohona Sarkar24, James Messing, Maria D. Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B. Perkerson, Aishe Kurti, Billie J. Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R. Hsiung, Charles Krieger, Melissa E. Murray, Masato Kato, John D. Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A. Zivkovic, Veronica Hirsch-Reinshagen, Raymond P. Roos, Stephan Züchner, Neill R. Graff-Radford, Ronald C. Petersen, Richard J. Caselli, Zbigniew K. Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W. Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B. Boylan, J. Paul Taylor, and Rosa Rademakers in Cell Research. Published online August 16 2017 doi:10.1016/j.neuron.2017.07.025

Cite This NeuroscienceNews.com Article
St. Jude Children’s Research Hospital “Fundamental ALS Pathology Discovered.” NeuroscienceNews. NeuroscienceNews, 19 August 2017.
<http://neurosciencenews.com/als-pathology-7333/>.
St. Jude Children’s Research Hospital (2017, August 19). Fundamental ALS Pathology Discovered. NeuroscienceNew. Retrieved August 19, 2017 from http://neurosciencenews.com/als-pathology-7333/
St. Jude Children’s Research Hospital “Fundamental ALS Pathology Discovered.” http://neurosciencenews.com/als-pathology-7333/ (accessed August 19, 2017).

Abstract

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

Highlights
•Mutations affecting the low-complexity domain of TIA1 cause ALS and ALS-FTD
•ALS-linked TIA1 mutations share a neuropathological TDP-43 signature
•TIA1 mutations promote phase separation and impair stress granule dynamics
•TDP-43 recruited to poorly dynamic stress granules becomes immobile and insoluble

Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10−6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

“TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics” by Ian R. Mackenzie, Alexandra M. Nicholson, Mohona Sarkar24, James Messing, Maria D. Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B. Perkerson, Aishe Kurti, Billie J. Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R. Hsiung, Charles Krieger, Melissa E. Murray, Masato Kato, John D. Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A. Zivkovic, Veronica Hirsch-Reinshagen, Raymond P. Roos, Stephan Züchner, Neill R. Graff-Radford, Ronald C. Petersen, Richard J. Caselli, Zbigniew K. Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W. Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B. Boylan, J. Paul Taylor, and Rosa Rademakers in Cell Research. Published online August 16 2017 doi:10.1016/j.neuron.2017.07.025

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