Neurodegenerative diseases, such as Alzheimer’s disease and dementia, are medical conditions that entail the progressive loss of neurons and a decline in brain function. Past studies have found a link between these diseases and the buildup of misfolded proteins, such as tau and α-synuclein.
Tau is a protein found primarily in neurons that typically helps to stabilize structures that transport nutrients and molecules within neurons, known as microtubules. α-synuclein, on the other hand, is a small protein located at the tips of neurons (i.e., pre-synapses), which typically helps to regulate the function of synaptic vesicles, small sacs that release neurotransmitters across synapses.
While these proteins have an important function in the healthy brain, their abnormal aggregation has been found to be a hallmark of several neurodegenerative diseases. The molecular processes that prompt their accumulation, however, have not yet been fully elucidated.
Researchers at Washington University in St. Louis and University of California recently investigated the role of a newly uncovered RNA molecule, called FAM151B-DT, in the aggregation of tau and α-synuclein proteins. Their findings, published in Molecular Psychiatry, suggest that this RNA is a key regulator of protein homeostasis, or in other words, that it helps to keep a balance in the production and degradation of proteins in the brain.
“Neurodegenerative diseases share common features of protein aggregation along with other pleiotropic traits, including shifts in transcriptional patterns, neuroinflammation, disruption in synaptic signaling, mitochondrial dysfunction, oxidative stress, and impaired clearance mechanisms like autophagy,” wrote Arun Renganathan, Miguel A. Minaya and their colleagues in their paper.
“However, key regulators of these pleiotropic traits have yet to be identified. We used transcriptomics, mass spectrometry, and biochemical assays to define the role of a novel lncRNA on tau pathophysiology.”
A previously unknown RNA implicated in protein aggregation
As part of their study, Renganathan and his colleagues examined stem cells and tissue samples using a wide range of genetic and experimental tools. Specifically, they compared the levels of the protein lncRNA in brain tissues derived from individuals who were diagnosed with a neurodegenerative disease to those of people who were not.
“We discovered a long non-coding RNA (lncRNA), FAM151B-DT, that is reduced in a stem cell model of frontotemporal lobar dementia with tau inclusions (FTLD-tau) and in brains from FTLD-tau, progressive supranuclear palsy, Alzheimer’s disease, and Parkinson’s disease patients,” wrote Renganathan and their colleagues. “We show that silencing FAM151B-DT in vitro is sufficient to enhance tau and α-synuclein aggregation.”
The researchers grew stem cells in the lab and then silenced the protein that they identified in these cells. Notably, they found that this heightened the aggregation of proteins associated with various neurodegenerative diseases.
“To begin to understand the mechanism by which FAM151B-DT mediates tau aggregation and contributes to several neurodegenerative diseases, we deeply characterized this novel lncRNA and found that FAM151B-DT resides in the cytoplasm where it interacts with tau, α-synuclein,” wrote the authors. “HSC70, and other proteins involved in protein homeostasis. When silenced, FAM151B-DT blocks autophagy, leading to the accumulation of tau and α-synuclein.”
Informing the treatment of neurodegenerative diseases
Overall, the results of this recent study suggest that the RNA molecule FAM151B-DT is of key importance for the balancing of tau and α-synuclein proteins in cells. Silencing this molecule seems to prompt the undesirable aggregation of proteins linked to neuronal damage and the emergence of neurodegenerative diseases.
The insight gathered by Renganathan and their colleagues could improve the present understanding of various neurodegenerative diseases. In the future, the molecule they identified could prove to be a promising target for treating these diseases early or addressing some of their symptoms.
“Importantly, we discovered that increasing FAM151B-DT expression is sufficient to promote autophagic clearance of phosphorylated tau and α-synuclein, and reduce tau and α-synuclein aggregation,” wrote the authors. “Overall, these findings pave the way for further exploration of FAM151B-DT as a promising molecular target for several neurodegenerative diseases.”