Protein Droplets Stimulate Neurodegenerative Fibril Clumping
By LabMedica International staff writers Posted on 03 May 2018 |
Image: Dense FUS protein fibrils form in the absence of nuclear-import receptors (NIRs, left), but are disrupted when NIRs are present (right) (Photo courtesy of Dr. James Shorter, University of Pennsylvania).
A team of neurodegenerative disease researchers has identified a molecular mechanism that prevents or reverses the formation of insoluble protein aggregates that characterize several brain disorders, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
Members of the class of RNA-binding proteins (RBPs) with prion-like domains (PrLDs) experience a phase transition to a functional liquid form. In this form, RBPs can mature into abnormal hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders. Furthermore, several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mistakenly associate with cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibril formation and cause disease.
Investigators at the University of Pennsylvania (Philadelphia, USA) investigated the role of RBPs in the neurodegenerative disease process. They reported in the April 19, 2018, online edition of the journal Cell that nuclear-import receptors (NIRs) specifically chaperoned and potently disaggregated wild-type and disease-linked RBPs bearing a nuclear-localization sequence (NLS). A nuclear localization sequence is an amino acid signal that "tags" a protein for import into the cell nucleus by nuclear transport.
The investigators added NIRs to aggregates of TDP-43 and FUS proteins. They found that by increasing the concentration of NIRs in vitro, clumps of RBPs quickly dissolved. NIRs also dissolved cytoplasmic clumps in cells, and functional RBPs were returned to the nucleus. In addition, when the expression of NIRs was increased in fruit fly disease models, lifespan of the insects was extended and degeneration was reduced.
“Clumps that form from these disease proteins are composed of sticky fibrils that damage nerve cells,” said senior author Dr. James Shorter, associate professor of biochemistry and biophysics at the University of Pennsylvania. “We want to reverse the formation of these clumps and put the RNA-binding proteins back in their proper place, inside the nucleus.”
Related Links:
University of Pennsylvania
Members of the class of RNA-binding proteins (RBPs) with prion-like domains (PrLDs) experience a phase transition to a functional liquid form. In this form, RBPs can mature into abnormal hydrogels composed of pathological fibrils that underpin fatal neurodegenerative disorders. Furthermore, several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mistakenly associate with cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibril formation and cause disease.
Investigators at the University of Pennsylvania (Philadelphia, USA) investigated the role of RBPs in the neurodegenerative disease process. They reported in the April 19, 2018, online edition of the journal Cell that nuclear-import receptors (NIRs) specifically chaperoned and potently disaggregated wild-type and disease-linked RBPs bearing a nuclear-localization sequence (NLS). A nuclear localization sequence is an amino acid signal that "tags" a protein for import into the cell nucleus by nuclear transport.
The investigators added NIRs to aggregates of TDP-43 and FUS proteins. They found that by increasing the concentration of NIRs in vitro, clumps of RBPs quickly dissolved. NIRs also dissolved cytoplasmic clumps in cells, and functional RBPs were returned to the nucleus. In addition, when the expression of NIRs was increased in fruit fly disease models, lifespan of the insects was extended and degeneration was reduced.
“Clumps that form from these disease proteins are composed of sticky fibrils that damage nerve cells,” said senior author Dr. James Shorter, associate professor of biochemistry and biophysics at the University of Pennsylvania. “We want to reverse the formation of these clumps and put the RNA-binding proteins back in their proper place, inside the nucleus.”
Related Links:
University of Pennsylvania
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