Myelin loss in C9orf72 hexanucleotide expansion carriers
Por:
Sirisi, S, Querol-Vilaseca, M, Dols-Icardo, O, Pegueroles, J, Montal, V, Munoz, L, Torres, S, Ferrer-Raventos, P, Iulita, MF, Sanchez-Aced, E, Blesa, R, Illan-Gala, I, Molina-Porcel, L, Borrego-Ecija, S, Sanchez-Valle, R, Clarimon, J, Belbin, O, Fortea, J, Lleo, A
Publicada:
1 oct 2022
Ahead of Print:
1 jun 2022
Resumen:
The most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the hexanucleotide repeat expansion in C9orf72. An important neuropathological hallmark associated with this mutation is the accumulation of the phosphorylated form of TAR (trans-activation response element) DNA-binding protein 43 (pTDP-43). Glia plays a crucial role in the neurodegeneration observed in C9orf72-associated disorders. However, less is known about the role of oligodendrocytes (OLs). Here, we applied digital neuropathological methods to compare the expression pattern of glial cells in the frontal cortex (FrCx) of human post-mortem samples from patients with C9-FTLD and C9-FTLD/ALS, sporadic FTLD (sFTLD), and healthy controls (HCs). We also compared MBP levels in CSF from an independent clinical FTD cohort. We observed an increase in GFAP, and Iba1 immunoreactivity in C9 and sFTLD compared to controls in the gray matter (GM) of the FrCx. We observed a decrease in MBP immunoreactivity in the GM and white matter (WM) of the FrCx of C9, compared to HC and sFTLD. There was a negative correlation between MBP and pTDP-43 in C9 in the WM of the FrCx. We observed an increase in CSF MBP concentrations in C9 and sFTLD compared to HC. In conclusion, the C9 expansion is associated with myelin loss in the frontal cortex. This loss of MBP may be a result of oligodendroglial dysfunction due to the expansion or the presence of pTDP-43 in OLs. Understanding these biological processes will help to identify specific pathways associated with the C9orf72 expansion.
Filiaciones:
Sirisi, S:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Querol-Vilaseca, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Dols-Icardo, O:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Pegueroles, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Montal, V:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Munoz, L:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Torres, S:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Ferrer-Raventos, P:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Iulita, MF:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Sanchez-Aced, E:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Blesa, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Illan-Gala, I:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Molina-Porcel, L:
Inst Invest Biomed August Pi & Sunyer, Neurol Tissue Bank Biobanc, Hosp Clin IDIBAPS, Barcelona, Spain
Borrego-Ecija, S:
Univ Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Serv Neurol, Hosp Clin,Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain
Sanchez-Valle, R:
Inst Invest Biomed August Pi & Sunyer, Neurol Tissue Bank Biobanc, Hosp Clin IDIBAPS, Barcelona, Spain
Univ Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Serv Neurol, Hosp Clin,Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Belbin, O:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Fortea, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
Lleo, A:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Memory Unit, Neurol Dept, St Quinti 77, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, St Quinti 77, Barcelona 08041, Spain
Network Ctr Biomed Res Neurodegenerat Dis CIBERNE, Madrid, Spain
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