Summary: A current research reveals that the dangerous trimer shape of the peptide SOD1 affects the brain, spinal cord, and muscle cells separately in Und, shedding light on its sophisticated growth.
The study found SOD1 trimers bind uniquely to different proteins in each tissue type, potentially impacting cellular communication, structure, and energy production. For instance, SOD1 trimers in neurons affect cellular aging and communication, while in muscle cells, they disrupt metabolic processes.
Researchers identified septin-7 as a protein that binds to SOD1 trimers in neurons, potentially exacerbating neurodegeneration. Septin-7 as a therapeutic target for ALS is now open for investigation thanks to this discovery. To understand how these interactions might influence the development of new treatments, further research is required.
Title:
New Clues in ALS: Toxic Protein May Uniquely Affect Brain, Spine, Muscles
Summary:
A recent study reveals that the toxic trimer form of the protein SOD1 affects the brain, spinal cord, and muscle tissues differently in ALS, shedding light on its complex progression. The study found SOD1 trimers bind uniquely to different proteins in each tissue type, potentially impacting cellular communication, structure, and energy production. For instance, SOD1 trimers in neurons affect cellular aging and communication, while in muscle cells, they disrupt metabolic processes. Researchers identified septin-7 as a protein that binds to SOD1 trimers in neurons, potentially exacerbating neurodegeneration. Septin-7 as a therapeutic target for ALS is now open for investigation thanks to this discovery. To understand how these interactions might influence the development of new treatments, further research is required.
Key Facts:
- SOD1 trimers bind differently in brain, spinal cord, and muscle tissues, affecting each uniquely.
- In neurons, SOD1 trimers impact cellular aging and connectivity, while in muscles, they interfere with metabolism.
- Septin-7, a key protein in neuron communication, may be disrupted by SOD1 trimers, suggesting it as a potential therapeutic target.
Source: Penn State
A new study by a team of researchers from Penn State College of Medicine found that a toxic version of a particular protein may have different effects on the brain, spinal cord, and skeletal muscle tissues, leading to the complex development and progression of amyotrophic lateral sclerosis ( ALS ).
The study represents a significant advance in the study’s investigation into the physiological mechanisms that could lead to ALS, as well as a potential therapeutic target for ALS treatments in the future.
The team , published , their findings in the journal , Structure.
” In ALS, like other , neurodegenerative diseases, there are proteins that tend to aggregate in harmful clusters. Superoxide dismutase 1, or SOD1,” as one of the associated compounds with ALS,” according to senior author Nikolay Dokholyan, G. Thomas Passananti Professor of Biochemistry and Professor of Biochemistry at the Penn State College of Medicine.
Dokholyan explained that SOD1 typically exists as a dimer, a , protein , composed of two identical units. Under certain conditions, SOD1 will change its shape and reassemble itself into a three-unit form called a trimer.
” We need to understand how the SOD1 trimers kill cells and the mechanisms involved, “he said.
ALS is a progressive neurodegenerative disease that affects nerve cells, called neurons, in the central nervous system and leads to , muscle weakness , and atrophy. SOD1 mutations have been linked to about 20 % of ALS cases with a known genetic cause and a small proportion of cases with no known genetic link.
Previous studies have demonstrated that SOD1 trimers appear to have a more toxic function than dimers. SOD1 trimers are linked with increased , cell death , in models of ALS but the exact molecular mechanism behind it is n’t known, Dokholyan said.
To investigate the role SOD1 trimers play in cell dysfunction and degeneration, the team examined which proteins bind with SOD1 trimers.
Dokholyan explained that they put SOD1 trimers in three different mouse tissue types: brain, spinal cord, and muscle, and that they had observé which proteins were attached to the trimers. Then, they compared the protein binding partners of SOD1 dimers in the three tissues to those of SOD1 trimers.
Brianna Hnath, PhD candidate in biomedical engineering at Penn State and co-author of the study, said,” We were trying to see if there were any new proteins that could show up interacting with this toxic protein that had n’t been seen before.
The purpose of the investigation was to determine the potential pathways through which this SOD1 trimer might have a toxic pathway.
The researchers claimed that the complex and multifaceted nature of ALS may be explained by the way that SOD1 trimers interact with various proteins depending on the type of tissue.
In brain and , spinal cord , tissue, SOD1 trimers bind with proteins that are involved in maintaining neuron structure, function and communication between , nerve cells. SOD1 trimers also activated cellular aging pathways that may be responsible for neuronal dysfunction and degeneration, according to the study.
In , muscle tissue, SOD1 trimers were found to bind with proteins involved with metabolic processes. In consequence, this interaction may directly affect muscle cell metabolism and energy production.
According to Nath,” The fact that we were finding different hits in the three different types of tissues, rather than one uniform hit,” suggests that there could be different mechanisms causing cell dysfunction and death depending on the type of tissue.
This finding challenges the traditional notion that muscle wasting in ALS is a secondary result of motor neuron degeneration—when these neurons do n’t function normally, muscle cells are n’t stimulated, which can lead to muscle atrophy, Dokholyan explained.
However, the study suggests that there may also be processes within muscle cells that are disrupted by SOD1 trimers that may cause muscle , cell dysfunction , and death, contributing to muscle wasting and neuron death.
” Both neurons and , muscle cells , are affected,” Dokholyan said”. On the neuron side, it’s potentially affecting the ability of neurons to connect to muscle, while on the muscle side, it affects metabolism.”
In particular, the study identified the protein septin-7 as a binding partner for SOD1 trimers but not native SOD1 dimers. Septin-7 has been linked to ALS in previous studies and plays a role in essential nerve cell processes like maintaining cellular structure and communication. Binding with SOD1 may disrupt these functions, leading to neuron degeneration.
It raises the question if addressing this interaction could slow or disrupt ALS progression, making septin-7 a potential therapeutic target, Dokholyan said.
He emphasized that more research is required to better understand the potential roles of SOD1 trimers in ALS, how it might cause cellular dysfunction and death, and the specific role of septin-7, which might influence the development of new treatments.
About this news from genetics and ALS research
Author: Christine Yu
Source: Penn State
Contact: Christine Yu – Penn State
Image: The image is credited to Neuroscience News
Original Research: Open access.
” Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells” by Esther Sue Choi et al. Structure
Abstract
Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells
In amyotrophic lateral sclerosis ( ALS ) models, misfolded species of superoxide dismutase 1 ( SOD1 ) are more fatal than aggregates of insoluble protein aggregates. Although it is unknown how structurally independent SOD1 trimers may contribute to cellular toxicity, disease pathology may be a factor.
Here, we uncovered the SOD1 trimer interactome—a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle.
We found that trimers may have an impact on normal cellular functions like dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We identified binding partners and key pathways that are related to SOD1 trimers.
We discovered SOD1 trimer-selective enrichment of genes. We performed thorough computational and biochemical analysis of the binding site of the SOD1 trimer protein to septin-7.
Our investigation uncovers important proteins and pathways within distinct tissues, allowing for a plausible interaction between genetic and pathophysiological mechanisms in ALS through SOD1 trimers interactions.
