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| Acta neuropathologica communications. 2022 Feb 12. doi: 10.1186/s40478-022-01314-x. pii: 10.1186/s40478-022-01314-x |
| A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics. |
| Nicolas G1, Sévigny M2, Lecoquierre F3, Marguet F4, Deschênes A5, Del Pelaez MC6, Feuillette S7, Audebrand A8, Lecourtois M9, Rousseau S10, Richard AC11, Cassinari K12, Deramecourt V13, Duyckaerts C14, Boland A15, Deleuze JF16, Meyer V17, Clarimon Echavarria J18, Gelpi E19, Akiyama H20, Hasegawa M21, Kawakami I22, Wong TH23, Van Rooij JGJ24, Van Swieten JC25, Campion D26, Dutchak PA27, Wallon D28, Lavoie-Cardinal F29, Laquerrière A30, Rovelet-Lecrux A31, Sephton CF32 |
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Abstract Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient's brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression. |
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© 2022. The Author(s). |
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KEYWORDS: Cytoplasmic granules, De novo mutation, FTLD-FET, FUS (fused in sarcoma), Frontotemporal dementia (FTD), Genetic variant, NCDN (neurochondrin), Neurodegeneration, Norbin, mGluR1/5 |
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Publikations ID: 35151370 Quelle: öffnen |
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