Discovery of Link Between Cellular Hallmarks of ALS May Lead to New Therapies

Discovery of Link Between Cellular Hallmarks of ALS May Lead to New Therapies
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By blocking the activity of the proteasome — a complex of enzymes responsible for the destruction of unnecessary or damaged proteins — dipeptide repeat (DPR) proteins associated with C9ORF72 gene repeat expansions (the most common genetic cause of amyotrophic lateral sclerosis) can travel between nerve cells and result in the buildup and mislocalization of TDP-43, a study has found.

Boosting the activity of the proteasome or targeting these DPR proteins with neutralizing antibodies may be promising therapeutic strategies for ALS, researchers noted.

These findings were reported in the study, “Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS/FTD,” published in The Embo Journal.

Sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurological disorders characterized by the progressive accumulation of TDP-43, a protein that normally binds and stabilizes RNA, inside the cytoplasm of nerve cells. This is accompanied by a gradual depletion of TDP-43 in the nuclei due to a defect in cellular transport. (The cytoplasm includes all the material found inside cells, whereas the nuclei are the compartments that hold a cell’s genetic information.)

The same phenomenon of TDP-43 accumulation and mislocalization inside nerve cells has been reported in patients with familial ALS.

“However, (…) the cause of the pathological [disease-causing] TDP‐43 mislocalization and aggregation in familial and sporadic cases remains elusive,” the researchers wrote.

Now, investigators at the German Center for Neurodegenerative Diseases found that DPR proteins produced from C9ORF72 gene repeat expansions, more specifically poly‐GA peptides, can travel between nerve cells, impairing the function of the proteasome, and ultimately leading to the accumulation and mislocalization of TDP-43 inside nerve cells.

In their experiments, the team used lab-cultured rat neurons in which they inserted poly-GA peptides linked to a green fluorescent protein so that they could be followed inside cells over time. Then they placed these modified neurons side by side with unmodified neurons that did not contain the poly-GA peptides.

After four days, they found that all neurons had poly-GA peptides, as well as high amounts of TDP-43 in their cytoplasm. However, when they treated cultured cells with an antibody against the poly-GA peptides, they found that “donor” neurons could no longer transmit the poly-GA peptides to “recipient” neurons.

Besides blocking the transmission of poly-GA peptides, the neutralizing antibody also reduced the mislocalization of TDP-43 in both “donor” and “recipient” neurons, indicating that even at low levels, poly-GA peptides were directly responsible for both the buildup and mislocalization of TDP-43 inside nerve cells.

They also found that poly-GA peptides disrupted the normal activity of the proteasome in both “donor” and “recipient” neurons, also contributing to the buildup and mislocalization of TDP-43 inside cells. However, when they treated cultured cells with rolipram, a proteasome activator, they found that treatment lessened both the accumulation of poly-GA peptides and TDP-43 inside neurons.

“Together, this work links [proteasome] dysfunction due to poly‐GA aggregation with the deficits in nucleocytoplasmic transport [of TDP-43] recently reported in C9orf72 FTD/ALS and other neurodegenerative diseases,” the researchers wrote.

“Our work indicates that boosting proteasome activity or targeting poly‐GA with antibodies may be a promising therapeutic strategy because it reduces not only poly‐GA aggregation but also TDP‐43 mislocalization and aggregation,” they added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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