Eleven years after the Ice Bucket Challenge brought ALS into the public spotlight, the neurodegenerative disease is once again drawing scientific attention—this time through the lens of CRISPR and single-cell genomics. A new study published in Nature Communications, “Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS,” offers fresh insight into how ALS begins, long before muscle weakness sets in.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, causes the progressive degeneration of motor neurons—the nerve cells that control muscles. Despite decades of research, ALS remains incurable, with most patients surviving only three to five years after diagnosis. While the disease can arise sporadically, about 10–20% of cases are inherited and linked to gene mutations in FUS, TARDBP, SOD1, or C9orf72.
What has puzzled researchers is how such diverse mutations all lead to the same outcome: the death of motor neurons. This study set out to answer that question using cutting-edge biotechnology.
The team used CRISPR-Cas9 to engineer several ALS-causing mutations—including FUS P525L, FUS R495X, and TARDBP M337V—into human induced pluripotent stem cells (iPSCs). These stem cells were then differentiated into two types of neurons: vulnerable motor neurons and more resilient interneurons.
With the help of single-cell RNA sequencing, the scientists tracked transcriptional changes in each cell type at high resolution. What they found was striking: motor neurons showed early and profound gene expression changes across all ALS models, while interneurons remained relatively unaffected.
These changes were especially pronounced in genes related to mitochondrial function—the cell’s energy producers.
The team discovered a consistent disease signature across mutations that pointed to early mitochondrial dysfunction in motor neurons. Even before hallmark signs of ALS like protein mislocalization emerged, mitochondria in ALS-affected neurons were impaired. Their movement along axons was disrupted, and key components of the mitochondrial respiratory chain were downregulated.
Importantly, by comparing mutations to a FUS knockout line, the researchers demonstrated that many of these effects stemmed from toxic gain-of-function, rather than simple loss of normal protein activity. “…we have now been able to show for the first time that most errors arising are caused by a new toxic property of the protein, not by a loss of function,” said first author Christoph Schweingruber, PhD.
This convergence on mitochondrial vulnerability—observed across FUS, TARDBP, and C9orf72 datasets—suggests a common early pathway in ALS pathogenesis.
While this work was performed in iPSC-derived neurons in vitro, it opens the door for earlier diagnostic tools and broader-acting therapeutics aimed at restoring mitochondrial function in ALS.
“We are trying to understand how these early errors occur in the sensitive motor neurons in ALS, and how it affects energy levels in the cells and their communication and necessary contacts with muscle fibers,” said senior author Eva Hedlund, PhD. “We believe that these are important keys to the understanding of why the synapses between motor neurons and muscles are broken in ALS and also to identify new targets for therapies.”
As interest in ALS is rekindled across public and scientific communities alike, studies like this one highlight the power of precision biotechnology to map the earliest footprints of disease. By revealing vulnerabilities shared across genetic forms of ALS, this research brings us closer to a future where gene editing and precision profiling may light the way toward treatments that benefit all patients, no matter the mutation.
For more news about CRISPR, join us for The State of CRISPR and Genome Editing virtual summit.
The post Potential ALS Mitochondrial Target Identified with CRISPR, scRNA-seq appeared first on GEN - Genetic Engineering and Biotechnology News.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, causes the progressive degeneration of motor neurons—the nerve cells that control muscles. Despite decades of research, ALS remains incurable, with most patients surviving only three to five years after diagnosis. While the disease can arise sporadically, about 10–20% of cases are inherited and linked to gene mutations in FUS, TARDBP, SOD1, or C9orf72.
What has puzzled researchers is how such diverse mutations all lead to the same outcome: the death of motor neurons. This study set out to answer that question using cutting-edge biotechnology.
CRISPR gets to the root
The team used CRISPR-Cas9 to engineer several ALS-causing mutations—including FUS P525L, FUS R495X, and TARDBP M337V—into human induced pluripotent stem cells (iPSCs). These stem cells were then differentiated into two types of neurons: vulnerable motor neurons and more resilient interneurons.
With the help of single-cell RNA sequencing, the scientists tracked transcriptional changes in each cell type at high resolution. What they found was striking: motor neurons showed early and profound gene expression changes across all ALS models, while interneurons remained relatively unaffected.
These changes were especially pronounced in genes related to mitochondrial function—the cell’s energy producers.
Mitochondrial vulnerability and ALS progression
The team discovered a consistent disease signature across mutations that pointed to early mitochondrial dysfunction in motor neurons. Even before hallmark signs of ALS like protein mislocalization emerged, mitochondria in ALS-affected neurons were impaired. Their movement along axons was disrupted, and key components of the mitochondrial respiratory chain were downregulated.
Importantly, by comparing mutations to a FUS knockout line, the researchers demonstrated that many of these effects stemmed from toxic gain-of-function, rather than simple loss of normal protein activity. “…we have now been able to show for the first time that most errors arising are caused by a new toxic property of the protein, not by a loss of function,” said first author Christoph Schweingruber, PhD.
This convergence on mitochondrial vulnerability—observed across FUS, TARDBP, and C9orf72 datasets—suggests a common early pathway in ALS pathogenesis.
Energy to move forward
While this work was performed in iPSC-derived neurons in vitro, it opens the door for earlier diagnostic tools and broader-acting therapeutics aimed at restoring mitochondrial function in ALS.
“We are trying to understand how these early errors occur in the sensitive motor neurons in ALS, and how it affects energy levels in the cells and their communication and necessary contacts with muscle fibers,” said senior author Eva Hedlund, PhD. “We believe that these are important keys to the understanding of why the synapses between motor neurons and muscles are broken in ALS and also to identify new targets for therapies.”
As interest in ALS is rekindled across public and scientific communities alike, studies like this one highlight the power of precision biotechnology to map the earliest footprints of disease. By revealing vulnerabilities shared across genetic forms of ALS, this research brings us closer to a future where gene editing and precision profiling may light the way toward treatments that benefit all patients, no matter the mutation.
For more news about CRISPR, join us for The State of CRISPR and Genome Editing virtual summit.
The post Potential ALS Mitochondrial Target Identified with CRISPR, scRNA-seq appeared first on GEN - Genetic Engineering and Biotechnology News.