Titre :

A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics.

Auteur(s) :

Nicolas, G. [Auteur]
CHU Rouen
Sévigny, M. [Auteur]
Université Laval [Québec] [ULaval]
Lecoquierre, F. [Auteur]
Marguet, F. [Auteur]
Deschênes, A. [Auteur]
Del Pelaez, M. C. [Auteur]
Feuillette, S. [Auteur]
Audebrand, A. [Auteur]
Lecourtois, M. [Auteur]
Rousseau, S. [Auteur]
Richard, A. C. [Auteur]
Cassinari, K. [Auteur]
Deramecourt, Vincent [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Duyckaerts, C. [Auteur]
Boland, A. [Auteur]
Deleuze, J. F. [Auteur]
Meyer, V. [Auteur]
Clarimon Echavarria, J. [Auteur]
Gelpi, E. [Auteur]
Akiyama, H. [Auteur]
Hasegawa, M. [Auteur]
Kawakami, I. [Auteur]
Wong, T. H. [Auteur]
Van Rooij, J. G. J. [Auteur]
Van Swieten, J. C. [Auteur]
Campion, D. [Auteur]
Dutchak, P. A. [Auteur]
Wallon, D. [Auteur]
Lavoie-Cardinal, F. [Auteur]
Laquerrière, A. [Auteur]
Rovelet-Lecrux, A. [Auteur]
Sephton, C. F. [Auteur]
Université Laval [Québec] [ULaval]

Titre de la revue :

Acta Neuropathologica Communications

Nom court de la revue :

Acta Neuropathol Commun

Numéro :

20

Date de publication :

2022-02-16

ISSN :

2051-5960

Mot(s)-clé(s) :

FUS (fused in sarcoma)
Frontotemporal dementia (FTD)
NCDN (neurochondrin)
Norbin
Genetic variant
De novo mutation
FTLD-FET
Neurodegeneration
mGluR1/5
Cytoplasmic granules

Mot(s)-clé(s) en anglais :

Cytoplasmic granules
mGluR1/5
Neurodegeneration
FTLD-FET
De novo mutation
Genetic variant
Norbin
NCDN (neurochondrin)
Frontotemporal dementia (FTD)
FUS (fused in sarcoma)

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

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, ...
Lire la suite >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.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Date de dépôt :

2024-01-16T01:30:28Z
2025-01-08T09:59:34Z