Dysfunctional ALS Patient Skin-Derived Muscle Neurons Rescued by Kenpaullone

A new proof-of-concept study reports converting adult skin cells from ALS patients into muscle neurons without first transforming them into stem cells. The patient-derived muscle neurons were dysfunctional, but when treated with a small molecule, the team could restore neuronal function.

The use of induced pluripotent stem cells (iPSCs) has revolutionized research in many fields, allowing the transformation of skin cells from individual patients to other cell types harboring the disease-specific defects.

The technology depends on the backtracking of a cell development to attain an immature kind of cell with the potential to be transformed into other cell types. The method has proved superior to models using transgenic animals or post-mortem tissue and has contributed to valuable information about defects leading to ALS.

There are limitations to the technique, however, since derived motor neurons are more similar to fetal cells than to the flawed adult neurons typical of ALS.

The new study, “Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients,“ has overcome this issue by producing muscle neurons using adult skin cells without first transforming them to stem cells.

The report – published in the journal Cell Reports by Meng-Lu Liu and colleagues from the University of Texas Southwestern Medical Center – also describes pathological features of the patient-derived neurons.

The team first transformed skin cells called fibroblasts into functional muscle neurons. But when they repeated the process with cells derived from ALS patients, the cells did not look or function like the healthy neurons.

Mutations in the FUS gene in ALS led the FUS protein to become trapped outside the cell nucleus instead of being transferred to its nuclear position in spinal muscular neurons. The team observed that in ALS patients, FUS was normally distributed in the skin cells. But when the cells were transformed into muscle cells, FUS was trapped outside the nucleus, just as they are in ALS neurons.

Treating these cells with kenpaullone, a small molecule known to promote neuronal survival, could restore cellular function. The study’s authors state that more research is needed to understand how kenpaullone leads to the rescue of cell function, and this could lead to more information for the development of new ALS drugs.