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000285263 1001_ $$aHuber, Nadine$$b0
000285263 245__ $$aFrontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage.
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000285263 520__ $$aFrontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased cytosolic accumulation of TDP-43 and p62/SQSTM1 and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.
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000285263 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000285263 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000285263 650_7 $$2NLM Chemicals$$aSequestosome-1 Protein
000285263 650_7 $$2NLM Chemicals$$aSQSTM1 protein, human
000285263 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000285263 650_7 $$2NLM Chemicals$$aTARDBP protein, human
000285263 650_2 $$2MeSH$$aHumans
000285263 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000285263 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: pathology
000285263 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000285263 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000285263 650_2 $$2MeSH$$aFrontotemporal Dementia: metabolism
000285263 650_2 $$2MeSH$$aNeurons: metabolism
000285263 650_2 $$2MeSH$$aNeurons: pathology
000285263 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000285263 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000285263 650_2 $$2MeSH$$aDNA Damage: genetics
000285263 650_2 $$2MeSH$$aDNA Damage: physiology
000285263 650_2 $$2MeSH$$aSynapses: metabolism
000285263 650_2 $$2MeSH$$aSynapses: pathology
000285263 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000285263 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000285263 650_2 $$2MeSH$$aMale
000285263 650_2 $$2MeSH$$aFemale
000285263 650_2 $$2MeSH$$aSequestosome-1 Protein: metabolism
000285263 650_2 $$2MeSH$$aMiddle Aged
000285263 650_2 $$2MeSH$$aAged
000285263 650_2 $$2MeSH$$aDNA Repeat Expansion: genetics
000285263 650_2 $$2MeSH$$aBrain: metabolism
000285263 7001_ $$aHietanen, Tomi$$b1
000285263 7001_ $$00000-0002-6083-2402$$aHeikkinen, Sami$$b2
000285263 7001_ $$aShakirzyanova, Anastasia$$b3
000285263 7001_ $$aHoffmann, Dorit$$b4
000285263 7001_ $$00000-0002-4672-0850$$aRostalski, Hannah$$b5
000285263 7001_ $$0P:(DE-2719)2811729$$aDhingra, Ashutosh$$b6$$udzne
000285263 7001_ $$0P:(DE-2719)2812129$$aRodriguez-Nieto, Salvador$$b7$$udzne
000285263 7001_ $$aKärkkäinen, Sari$$b8
000285263 7001_ $$00000-0002-1646-9992$$aKoskuvi, Marja$$b9
000285263 7001_ $$aKorhonen, Eila$$b10
000285263 7001_ $$aHartikainen, Päivi$$b11
000285263 7001_ $$aPylkäs, Katri$$b12
000285263 7001_ $$00000-0003-4346-1133$$aKrüger, Johanna$$b13
000285263 7001_ $$00000-0002-9530-7472$$aMalm, Tarja$$b14
000285263 7001_ $$aTakalo, Mari$$b15
000285263 7001_ $$aHiltunen, Mikko$$b16
000285263 7001_ $$00000-0001-6559-1153$$aKoistinaho, Jari$$b17
000285263 7001_ $$aPortaankorva, Anne M$$b18
000285263 7001_ $$00000-0001-9940-9524$$aSolje, Eino$$b19
000285263 7001_ $$00000-0003-0959-2957$$aHaapasalo, Annakaisa$$b20
000285263 773__ $$0PERI:(DE-600)1502531-7$$a10.1038/s41380-025-03272-x$$gVol. 31, no. 3, p. 1500 - 1516$$n3$$p1500 - 1516$$tMolecular psychiatry$$v31$$x1359-4184$$y2026
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