Scientists ID key regulator that helps prevent toxic protein clumps

Discovery may open new therapeutic avenues for neurodegenerative diseases

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A scientist looks through a microscope on a table with a beaker and test tubes.

Scientists have discovered a new regulator — called NHR-49 — that may shed light and open potential new therapeutic avenues to prevent the formation of toxic protein clumps, a hallmark of aging-related diseases, including Parkinson’s disease.

Using embryos of the roundworm Caenorhabditis elegans, they found that NHR-49 is activated in response to stress and elicits pathways to promote cellular repair and proteostasis, the process by which cells maintain a healthy balance of correctly folded, functional proteins and eliminate misfolded or damaged ones.

The findings may hold promise for the development of new strategies to halt the progression of diseases like Parkinson’s, which is marked by the loss of proteostasis. This loss is believed to contribute to the accumulation of toxic clumps of alpha-synuclein protein, a disease hallmark.

“Our work is really trying to understand in aging what are the earliest events that we can detect to restore proteostasis, because proteostasis controls the health of every protein,” Richard Morimoto, PhD, director of the Daniel F. and Ada L. Rice Institute at Northwestern University, in Evanston, Illinois, and the study’s lead author, said in a university news story. “The proteostasis network that controls protein synthesis, folding and clearance is the only cellular pathway that we know of that can prevent or enhance the clearance of amyloid formation.”

The study, “Nuclear receptor signaling via NHR-49/MDT-15 regulates stress resilience and proteostasis in response to reproductive and metabolic cues,” was published in the journal Genes & Development.

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Disruption of proteostasis plays significant role in Parkinson’s onset, progression

In Parkinson’s disease, the disruption of proteostasis is known to play a significant role in the onset and progression of the condition. This disrupted balance leads to the formation of toxic clumps of misfolded alpha-synuclein protein, ultimately resulting in the death of nerve cells and contributing to the disease’s characteristic symptoms.

All cells in the body have in-built mechanisms to respond to insults that lead to the loss of proteostasis. Such mechanisms are particularly active during the early phases of embryonic development and decline with age.

Now, using C. elegans as a model organism, Morimoto and his team discovered a new mechanism of how a damaged embryo protects the mother from stressors that may culminate with the loss of proteostasis.

The team had previously shown that damages to the embryonic vitelline layer — the outer shell of the egg — trigger the release of signals from the embryo to the mother to prevent the loss of proteostasis and suppress protein aggregation.

“It was stunning. It was, in a sense, a novel form of transgenerational signaling,” Morimoto said. “That was intriguing because this is about communicating from one tissue, the egg, to the mother.”

In the new study, the researchers found that in C. elegans embryos, NHR-49, a protein known to regulate the activity of certain genes, was an important regulator of proteostasis. Specifically, they discovered NHR-49 is activated in response to embryonic damage, triggering fat metabolism, especially the breakdown of fatty acids. This metabolic process not only serves as an energy source but also supports cellular repair and maintenance, ultimately promoting overall cellular health.

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NHR-49 is key regulator of fat balance and cellular resilience

These findings establish NHR-49 as a key regulator of fat balance and cellular resilience to insults that would promote the loss of proteostasis. The NHR-49 signaling pathway is a potential biomarker of proteostasis and a potential therapeutic target for preventing its loss, according to the researchers.

“The major emphasis for the future is to now convert this into predictable models that for which we could then target that pathway or that set of genes,” Morimoto said. “Our ability to identify the machinery and understand what is optimal allows us to then understand how to rejuvenate the cell, the tissue, and the organism against the threats of aging.”

The study was supported by a $32.4-million grant from the Hevolution Foundation awarded to Morimoto to study the mechanisms underlying the loss of proteostasis.