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Researchers at the University of Waterloo will use a CA$125,000 (about $93,000) grant from the <a href="https://als.ca">ALS Society of Canada</a> and <a href="https://braincanada.ca/">Brain Canada</a> to better understand how proteins become misplaced in cells and build into the toxic clumps that mark <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Led by Dale Martin, PhD, an assistant professor of biology, the team is conducting in-depth studies into fatty acylation, a molecular process in which proteins are tagged with certain fatty molecules so they can be shipped to specific locations within cells. The goal is to find new targets for <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a>.
When fatty acylation goes awry, it can ship proteins to destinations other than those intended, making these proteins perform their functions in the wrong place. Problems in fatty acylation also can stop damaged proteins from traveling to cellular disposal sites, causing a toxic buildup that contributes to neurodegeneration.
Martin’s <a href="https://neurdyphagylab.squarespace.com">NeurdyPhagy lab</a> has been focusing on understanding how fatty acylation works, and how it might be involved in ALS.
[recommended-reading id=90256]
<h3>ALS Society, Brain Canada awarded two-year grants to eight research teams</h3>
In 2022, Lucia Liao, a PhD student at Martin&#8217;s lab, secured an ALS Canada–Brain Canada <a href="https://alsnewstoday.com/news/als-society-canada-brain-canada-early-stage-research-grants/">PhD grant worth $75,000</a>  to <a href="https://als.ca/research/als-canada-research-program/projects-funded/projects-funded-2022/">study how a type of fatty acylation</a> called palmitoylation contributes to the TDP-43 protein forming toxic clumps, a feature seen in nearly all ALS patients.
“These research funds will help us delve deeper into some of the earliest molecular mechanisms that go awry in ALS and set the foundation for continuing ALS research in the NeurdyPhagy lab,” Martin said in a <a href="https://uwaterloo.ca/science/news/professor-dale-martin-receives-grant-explore-new-therapeutic">university press release</a>.
To date, the lab reports having &#8220;pinpointed key proteins involved in ALS that undergo acylation.&#8221;
<a href="https://alsnewstoday.com/causes-of-als/">ALS occurs</a> when motor neurons — the nerve cells that control voluntary movement — become damaged, causing <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">disease symptoms</a> characterized by progressive and bodywide muscle weakness.
An ALS hallmark is the buildup of misfolded proteins that are toxic to these neurons. This is thought to happen, at least in part, by key proteins being misdirected to sites within the nerve cells.
For example, the TDP-43 protein is normally found within the cell nucleus. But in ALS it tends to accumulate in the cytoplasm, the semifluid substance that fills a cell outside its nucleus, where <a href="https://alsnewstoday.com/news/structure-tdp-43-protein-aggregates-characterize-als-identified-first-time/">TDP-43 forms toxic clumps</a> that prevent motor neurons from working properly.
While fatty acylation influences where proteins are located within cells, tagging proteins with fat can be undone to allow a proper redirection. Identifying what controls this switch may led to targets for therapies able to slow or stop <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a>.
“We’re grateful for this funding and I’m excited to provide an update to the ALS community at the ALS Canada Research Forum in April,” Martin said. The ALS Canada meeting is to take place on April 27–29 in Toronto.
Martin is one of eight researchers nationwide to win a two-year ALS Canada–Brain Canada 2023 Discovery Grant, for a total awarding of CA$1.35 million to support a range of work into ALS causes, diagnosis, and treatment.
“These projects represent Canada’s best new ideas to impact our current understanding of ALS,” David Taylor, PhD, vice president of research and strategic partnerships at ALS Canada, said in a <a href="https://braincanada.ca/announcements/discovery-grants-2023/">press release</a> from the nonprofit organization. “Our hope is that discoveries made through this funding will take us closer to effective treatments and, someday, a world free of ALS.”

ALS Society-Brain Canada grant aids work into protein clumping in ALS

<a href="https://www.vectorytx.com/" rel="nofollow">VectorY Therapeutics</a> has raised about $138 million in funding aiming to bring into clinical testing VTx-002, its lead treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS). The therapy equips nerve cells to produce antibodies against the damaging <a href="https://alsnewstoday.com/news/scientists-find-how-tdp-43-affects-important-nerve-protein-als/">TDP-43 protein clumps that are an ALS hallmark</a>.
“The investment will enable us to advance our lead program VTx-002, a potentially disease-modifying therapy for ALS, into clinical development. Our program is uniquely positioned to address TDP-43 pathology, which underlies the disease in the vast majority of ALS patients,” Sander van Deventer, CEO of VectorY, said in a <a href="https://www.vectorytx.com/news/vectory-raises-129-million-138-million-series-a-financing-to-advance-vectorized-antibody-programs-in-neurodegenerative-diseases">company press release</a>.
The accumulation of TDP-43 protein clumps in nerve cells is seen in about 97% of all ALS cases, and clearing these toxic molecules is regarded as a potential approach to delaying or preventing disease progression in nearly all patients.
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<h3>A faulty TDP-43 protein clumps in nerve cells of ALS patients</h3>
Antibodies are natural proteins made by the immune system that are able to bind a specific target. A few <a href="https://alsnewstoday.com/news/italian-researcher-granted-20k-tdp-43-antibody-research-als-treatment/">antibodies aimed at clearing misfolded TDP-43</a> proteins from nerve cells are in development.
However, traditional antibody-based therapies are usually too large and limited in their ability to reach the brain and spinal cord. They also require regular administrations, as infused antibodies eventually degrade and lose their effectiveness.
VectorY is developing <a href="https://www.vectorytx.com/vectorized-antibody-platform" rel="nofollow">vectorized antibodies</a>, a class of antibodies that essentially deliver the genetic sequence of an antibody to target cells, enabling them to produce their own therapeutic antibodies.
The platform uses harmless adeno-associated viruses (AAV) that were modified to be highly specific to cells in the brain and spinal cord. In VTx-002, that AAV carries a gene designed to enter cells, where it can be used to produce an antibody against the faulty TDP-43 protein, while leaving functional TDP-43 proteins unharmed.
Notably, because the virus stays inside cells until they die, a single administration of the therapy is expected to result in long-term antibody production and durable responses.
Proceeds from the Series A financing also will be used to boost the development of existing and new vectorized antibodies for other conditions marked by the buildup of toxic protein aggregates, diseases called proteinopathies that include <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington’s</a> and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s</a>.
“The series A will also support advancement of additional pipeline programs targeting proteinopathies in neurodegenerative diseases demonstrating the broad potential of our platform,” van Deventer said.
The financing round was co-led by EQT Life Sciences and the Forbion Growth Opportunities Fund, with the support of multiple new and past investors.
“We are very impressed with VectorY’s unique capabilities to combine gene and antibody therapy drug development with deep neuroscience expertise. The company’s technology allows for targeted protein degradation while restoring or preserving normal protein function, with applications across multiple neurodegenerative diseases,” said Arno de Wilde, director at EQT Life Sciences.
Previous and new finance round investors included MRL Ventures Fund, a corporate venture arm of Merck in the U.S., Insight Partners, ALS Investment Fund, Forbion Ventures, and BioGeneration Ventures.
“The Series A financing, supported by such a strong syndicate of European and US investors, is an endorsement of our pioneering approach &#8230; to bring much-needed therapies to patients with neurodegenerative diseases,” van Deventer said.
As part of the financing, de Wilde, Wouter Joustra, a partner at Forbion Growth Opportunities Fund, and Karin Kleinhans, a partner at MRL Ventures Fund, will join VectorY’s board of directors.

VectorY raises millions to support antibody gene therapy for ALS

When the TDP-43 protein is less able to form two-protein complexes called dimers, it appears to be more likely to form the toxic clumps seen in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study reports.
As these clumps are found in about 97% of all ALS cases, a better understanding of the mechanisms leading to TDP-43 protein aggregates may help in developing therapies for most patients.
&#8220;Maintaining the &#8230; equilibrium of these pathogenic proteins may represent a common therapeutic target for neurodegenerative diseases,&#8221; its researchers wrote.
The study, &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.adf6895">Monomerization of TDP-43 is a key determinant for inducing TDP-43 pathology in amyotrophic lateral sclerosis</a>,&#8221; published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
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<h3>Research into how TDP-43 aggregates in nerve cells of ALS patients</h3>
One of the key molecular features of ALS is the abnormal aggregates — clumps — of the protein TDP-43 in nerve cells. This protein normally is found in the nucleus — the cellular compartment that houses DNA — but in virtually all ALS cases, the protein instead forms <a href="https://alsnewstoday.com/news/als-study-links-abnormal-rna-modifications-tdp-43-function/">aggregates outside the nucleus</a>.
It&#8217;s thought that TDP-43 clumps disrupt normal nerve function and contribute to driving the disease. Exactly how these clumps form, however, remains incompletely understood.
Under normal circumstances, TDP-43 is found in two states in nerve cells. Either the protein exists as a monomer containing just one TDP-43 protein, or the protein exists in a dimer where two of the proteins are attached to each other.
Scientists set out to investigate whether changes in the monomer/dimer status of TDP-43 is disrupted in ALS, and whether such changes may play a role in the protein&#8217;s abnormal clumping.
They first conducted tests on nerve tissue collected from people with <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a>. Results showed that these tissues had more TDP-43 monomers, and correspondingly fewer dimers, than what&#8217;s normally seen in people without the disease.
More TDP-43 in its monomer state might help to trigger ALS-related molecular changes, findings implied. To test this idea, the researchers engineered nerve cells harboring a modified version of the TDP-43 protein — one not able to form dimers, so it only exists as a monomer unless it&#8217;s forming clumps.
Experiments in these cells showed that, when TDP-43 is only present as a monomer, it&#8217;s more likely to move outside of the nucleus into the cytoplasm and clump.
<h3>Lack of TDP-43 &#8216;monomer-dimer equilibrium&#8217; may occur early in ALS</h3>
Further experiments revealed clues as to the biochemical processes underlying these changes. Dysregulations in transcription — the initial process where a cell &#8220;reads&#8221; a gene — can lead to more TDP-43 in monomer form, the researchers found. The movement of TDP-43 from the cell nucleus to the cytoplasm also was seen to be regulated by another protein called Nxf1.
&#8220;TDP-43 monomerization induced its cytoplasmic mislocalization in an Nxf1-dependent manner, along with &#8230; aggregation of TDP-43, which is a pathological hallmark of ALS,&#8221; the scientists wrote.
These findings &#8220;may be important in future research on early pathogenic [disease-causing] events related to TDP-43 and in the search for early diagnostic markers,&#8221; they added.
&#8220;Our study showed that the disruption of TDP-43 monomer-dimer &#8230; equilibrium may be a relatively early change, followed by cytoplasmic mislocalization of monomeric TDP-43, leading to &#8230; sequestering of normal TDP-43 into aggregates,&#8221; the scientists concluded. &#8220;We speculate that this vicious cycle may exacerbate TDP-43 pathology.&#8221;

Tag: protein clumps

ALS Society-Brain Canada grant aids work into protein clumping in ALS

VectorY raises millions to support antibody gene therapy for ALS

TDP-43 more likely to clump if it can’t form two-protein complexes