The CRISPR gene editing tool has been revolionary for the research lab, and it has also been used to transform the lives of a handful of patients of a few genetic diseases. Now scientists have used CRISPR to learn more about the cellular dysfunction that underlies the neurodegenerative disorder ALS (amyotrophic lateral sclerosis). The findings have linked the disease to problems in the mitochondria, which are well known as the power-generating organelles of the cell, though they play other roles too. This work may also help pave the way for new ALS treatment options. The findings have been reported in Nature Communications.
In this study, the researchers analyzed the impact of various genetic mutations that lead to ALS, and found a common thread: mitochondrial dysfunction. The differemt mutations were introduced into a motor neuron model, and those cells were analyzed with single-cell RNA sequencing to identify the active genes.
The cells that die off in ALS, leading to many symptoms of the disease, are motor neurons, which help control movement. The initial pathology underlying ALS seemed to start in the mitochondria of these cells before any other problems arose, and in how they move in the cells as the neurons are demanding energy. This was a common problem among different genetic models of ALS.
“This means that there are common factors that could be targeted with drugs, regardless of the cause of the disease,” suggested senior study author Dr. Eva Hedlund of Stockholm University.
Some hypotheses have suggested that ALS is due to proteins that end up in the wrong place in cells, whike others have indicated that some ALS-linked mutations lead to a loss of protein functions. But this study has indicated that ALS-linked mutant proteins seem to gain new and problematic functions in ALS.
The investigators used CRISPR to mutate the FUS gene, for example, which has been associated with ALS. This has shown that it is not a loss of protein function, but new and incorrect properties of the protein FUS encodes for that are leading to ALS, the researchers noted.
The work also suggested that in cells that carry ALS-causing mutations, the movement of mitochondria into the axons of motor neurons was disrupted, compared to normal motor neurons. This seemed to happen regardless of whether the mutant proteins were in the wrong place in the cell or not.
This is a major problem for these cells, since there is a huge demand for the energy provided by mitochondria in axons. "Without them the nerve cells do not have enough energy to communicate properly with other cells,” said Hedlund.
“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. We believe that these are important keys to the understanding of why the synapses between motor neurons and muscles is broken in ALS and also to identify new targets for therapies,” Hedlund added.
Sources: Stockholm University, Nature Communications
