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The most common genetic cause of frontotemporal dementia triggers disturbances in the structure and function of neuronal synapses

Hexanucleotide repeat expansion in the C9orf72 gene, which causes frontotemporal dementia and the motoneuron disease ALS, leads to structural and functional changes in synapses that connect neurons, a new study conducted at the University of Eastern Finland shows.

Connections between neurons, or synapses, transmit information in the brain. Their undisturbed function is crucial for example for learning, memory, or movement. In the brains of patients with neurodegenerative diseases, synaptic dysfunction is thought to be one of the earliest pathological changes, leading to impairment of memory, learning, or behaviour, and ultimately to neuronal loss and dementia. Disturbances in different synaptic neurotransmitter systems, such as glutamatergic and GABAergic systems, have been observed in the brains of patients with frontotemporal dementia. However, the molecular mechanisms of these disturbances in clinically or genetically different frontotemporal patients are poorly known.

A study conducted in the group of Research Director Annakaisa Haapasalo at the University of Eastern Finland investigated the effects of the most common genetic alteration causing frontotemporal dementia and amyotrophic lateral sclerosis (ALS), the C9orf72 hexanucleotide repeat expansion, on synapses at the molecular and cellular level in mouse neuron cultures. Mouse neurons expressing the C9orf72 repeat expansion showed neuropathological changes similar to those seen in the repeat expansion-carrying frontotemporal dementia or ALS patients, i.e., expanded repeat-derived intranuclear RNA foci and dipeptide repeat-containing (DPR) proteins. DPR proteins were also found present in synapses. The study also showed that the repeat expansion led to decreased branching of the neurons and structural changes in dendritic spines. Dendritic spines are sites in the dendrites of neurons where most of the excitatory glutamatergic synapses are formed.

The observed structural changes in the neurons and synapses were found to be associated with increased sensitivity of the neurons to glutamate-mediated excitotoxic cell death and enhanced neuronal activity. The neurons expressing the C9orf72 repeat expansion were abnormally hyperactive. Molecular mechanistic studies showed that the hyperactivity of the neurons was due to the activity of extrasynaptic NMDA receptor subtypes. Extrasynaptic NMDA receptors have previously been shown to convey excitotoxic effects in neurons. The study was published in Neurobiology of Disease.

The effects of C9orf72 repeat expansion on synapses are the subject of the PhD thesis of the lead author, Early-Stage Researcher Nadine Huber.  “These interesting new results warrant further studies of the effects of the C9orf72 repeat expansion on synapses also in human neurons, as drugs that affect neurotransmitter systems are used to mitigate for example behavioural symptoms in patients with frontotemporal dementia. Detailed studies at the molecular level in neurons derived from patients harbouring different genetic mutations or showing different clinical features may in the future help to develop better drugs targeting synapses,” says Huber.

Huber was also the lead author of an extensive review article on neurotransmitter system disturbances and synaptic dysfunction as well as drugs affecting different neurotransmitter systems that are currently used to treat frontotemporal dementia patients. The review was recently published in Molecular Psychiatry.

Synaptic dysfunction in frontotemporal and other early-onset dementias are a key research topic in Haapasalo’s research group. The international SynaDeg project starting in 2022 and led by Haapasalo, which focuses on synaptic disturbances in early-onset dementias, was recently awarded EU JPND research funding. “The synaptic changes we described in mouse neurons expressing the C9orf72 repeat expansion provide an excellent basis for extending the studies next to induced pluripotent stem cell-derived neurons from clinically and genetically different early-onset dementia patients. In the SynaDeg project, we will study synaptic changes in both the patients' brains and their stem cell-derived neurons in cultures. In this way, we aim to understand the molecular mechanisms of early synaptic changes that may help us to identify new specific disease biomarkers and drug targets for the benefit of patients with frontotemporal and other early-onset dementias,” Haapasalo explains.

The main funders of the now published study were Academy of Finland, Sigrid Jusélius Foundation, ALS tutkimuksen tuki registered association (ALStuttu ry), and the UEF Doctoral Programme in Molecular Medicine (DPMM), in which Nadine Huber is an Early-Stage Researcher. The study is part of the research activities of the Finnish FinFTD frontotemporal dementia research network.

Haapasalo’s research group is also a member 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. Comprising 17 research groups, NEURO RC integrates biological neurosciences with data sciences, neuro-innovations, and neuro-ethics.

Website: https://www.uef.fi/en/research-community/neuroscience-neuro

Twitter: https://twitter.com/UEFneuroscience

More information:

Early-Stage Researcher Nadine Huber, MSc, University of Eastern Finland

Research Director Annakaisa Haapasalo, PhD, Adjunct Professor, University of Eastern Finland

Articles:

Huber N, Hoffmann D, Giniatullina R, Rostalski H, Leskelä S, Takalo M, Natunen T, Solje E, Remes AM, Giniatullin R, Hiltunen M, Haapasalo A. C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction. Neurobiology of Disease 162 (2022) 105584. https://doi.org/10.1016/j.nbd.2021.105584. Online ahead of print.

Huber N, Korhonen S, Hoffmann D, Leskelä S, Rostalski H, Remes AM, Honkakoski P, Solje E, Haapasalo A. Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration - Insights into disease mechanisms and current therapeutic approaches Molecular Psychiatry. 2021 Nov 19. https://doi.org/10.1038/s41380-021-01384-8. Online ahead of print.