Neurons produced from frontotemporal dementia patients’ skin biopsies using modern stem cell technology recapitulate the synaptic loss and dysfunction detected in the patients’ brains, a new study from the University of Eastern Finland shows.
Frontotemporal dementia is a progressive neurodegenerative disease affecting the frontal and temporal lobes of the brain. The most common symptoms are behavioral changes, difficulties in understanding or producing speech, problems in movement, and psychiatric symptoms. Often, frontotemporal dementia has no identified genetic cause, but especially in Finnish patients, hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause, present in about half of the familial cases and in 20 per cent of the sporadic cases where there is no family history of the disease. However, the disease mechanisms of the different forms of frontotemporal dementia are still poorly understood, and there are currently no effective diagnostic tests or treatments affecting the progression of the disease in clinical use.
Brain imaging and neurophysiological studies have shown that pathological and functional changes underlying the symptoms occur at synapses, the connections between brain neurons, in frontotemporal dementia patients. PET imaging studies have shown significant synapse loss in the brain, and transcranial magnetic stimulation, on the other hand, has indicated disturbed function of both excitatory and inhibitory neurotransmitter systems, leading to deficient neurotransmission. Often, drugs affecting the different neurotransmitter systems are used to mitigate the symptoms of frontotemporal dementia patients.
Protein accumulations, synaptic loss and disturbed neurotransmission
The new study utilised induced pluripotent stem cell-based neurons derived from skin biopsies of frontotemporal dementia patients. Neurons were produced both from frontotemporal dementia patients carrying the C9orf72 repeat expansion and from sporadic patients and compared to neurons generated from healthy individuals. The neuronal cultures contained both excitatory and inhibitory neuron types from all layers of the human cerebral cortex and, when cultured for a longer period of time, also astrocytes, important glial cells supporting the neurons appeared.
Neurons carrying the C9orf72 repeat expansion showed neuropathological RNA and DPR protein accumulations specifically associated with the repeat expansion. In addition, accumulation of p62 and TDP-43 proteins, typically found in the brains of frontotemporal dementia patients, were detected in the neurons of both sporadic and C9orf72 repeat expansion-carrying patients. “These findings indicated that the patient-derived neuronal model system developed in the study recapitulates the typical neuropathological changes detected in the brains of frontotemporal dementia patients,” says the Research Group Leader, Professor Annakaisa Haapasalo.
Studies related to synaptic structure and function found that the number of dendritic spines was significantly reduced in both C9orf72 repeat-expansion-carrying and sporadic patient neurons compared to healthy neurons. Dendritic spines are sites where the synapses between neurons are formed. “The findings suggest that synaptic loss in neurons of frontotemporal dementia patients can be modelled in these patient-derived neuronal cultures,” Postdoctoral Researcher Nadine Huber says.
In addition, when the neurons were stimulated with different neurotransmitters, it was found that frontotemporal dementia patient neurons responded more poorly to stimulation compared to control neurons, indicating disturbed neurotransmission.
Neurons try to compensate for synaptic changes
Gene expression analyses of the neurons revealed changes in genes and biological pathways involved in the regulation of synaptic structures and function as well as various neurotransmitter systems. The expression of several of these genes increased, which may indicate a mechanism by which the neurons are trying to compensate for the loss of synapses and the decline in synaptic function.
“We observed similar synaptic changes in the neurons of both sporadic and C9orf72 repeat expansion-associated frontotemporal dementia patients, suggesting that synapse loss and dysfunction are key underlying phenomena of the disease regardless of the patient's genetic background,” Haapasalo says.
The researchers expect further studies to reveal detailed molecular-level mechanisms underpinning the observed synaptic deficits, which may benefit the development of novel biomarkers and therapies for frontotemporal dementia.
“The preclinical disease model developed in this study will be utilised in the future to test the therapeutic effects of various drugs or electrical stimulation resembling the transcranial stimulation in patients.”
The study was carried out in the Molecular Neurodegeneration Research Group led by Haapasalo at UEF’s A.I. Virtanen Institute for Molecular Sciences. Huber was the principal investigator in the study, and several other research groups were involved from the University of Eastern Finland, Kuopio University Hospital, the Universities of Oulu and Helsinki, as well as the German Center for Neurodegenerative Diseases, DZNE.
The study received funding from the Sigrid Jusélius Foundation, the Research Council of Finland (FiNeFTD and SeekFTD projects) and the EU Joint Programme – Neurodegenerative Disease Research (JPND). The study is part of the JPND SynaDeg project, coordinated by Haapasalo, and the activities of the Finnish FinFTD research network.
The study was published in the prestigious Molecular Psychiatry journal.
For further information, please contact:
Professor Annakaisa Haapasalo, [email protected], https://uefconnect.uef.fi/en/annakaisa.haapasalo/
Postdoctoral Researcher Nadine Huber, [email protected] , https://uefconnect.uef.fi/en/nadine.huber/
Research article:
Huber et al. Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage. Mol Psychiatry. Published online September 26, 2025. doi:10.1038/s41380-025-03272-x
Haapasalo's research group is part of the multidisciplinary Neuroscience Research Community (NEURO-RC) at the University of Eastern Finland. NEURO RC aims to understand the disease-specific and common molecular mechanisms underlying neurodegenerative diseases and epilepsy and to identify novel biomarkers and therapeutic approaches for their prevention and cure. NEURO RC integrates biological neurosciences with data sciences, neuro-innovations, and neuro-ethics. Learn more and connect with NEURO RC:
