Belgian researchers have identified a new strategy for treating an inherited form of dementia after attempting to turn stem cells derived from patients into the neurons most affected by the disease.
Scientists found a targetable defect that prevents normal neurodevelopment in patient-derived stem cells carrying a mutation predisposing them to frontotemporal dementia.
These stem cells partially return to normal when the defect is corrected.
“Use of induced pluripotent stem cell (iPSC) technology makes it possible to model dementias that affect people later in life,” said senior study author Catherine Verfaillie of KU Leuven.
The technology involves taking skin cells from patients and reprogramming them into embryonic-like stem cells capable of turning into other specific cell types relevant for studying a particular disease.
Frontotemporal disorders are the result of damage to neurons in parts of the brain called the frontal and temporal lobes, gradually leading to behavioural symptoms or language and emotional disorders.
Mutations in a gene called progranulin (GRN) are commonly associated with frontotemporal dementia, but GRN mutations in mice do not mimic all the features of the human disorder, which has limited progress in the development of effective treatments.
“iPSC models can now be used to better understand dementia, and in particular frontotemporal dementia, and might lead to the development of drugs that can curtail or slow down the degeneration of cortical neurons,” Verfaillie said.
Verfaillie and Philip Van Damme of the Leuven Research Institute for Neuroscience and Disease created iPSCs from three patients carrying a GRN mutation.
These immature cells were impaired at turning into mature, specialised cells called cortical neurons – the most affected cell type in frontotemporal dementia.
One of the top defective pathways in the iPSCs was the Wnt signalling pathway, which plays an important role in neuronal development.
However, genetic correction or treatment with a compound that inhibits the Wnt signalling pathway restored the ability of the iPSCs to turn into cortical neurons.
Taken together, the findings demonstrate that the GRN mutation causes the defect in cortical neuron formation by altering the Wnt signalling pathway, researchers said.
The study appears in the journal Stem Cell Reports.