Portal de investigación
Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis
Fecha de publicación:
Autores de IBSAL
Autores ajenos a IBSAL
- Buondelmonte, C
- Burmistrova, O
- Bonora, N
- Alonso-Batan, P
- Fernandez, E
- Llop, J
- Ramos-Cabrer, P
- Sharaireh, A
- Guevara-Ferrer, M
- Fitzpatrick, L
- Thompton, CD
- McKay, TR
- Storch, S
- Medina, DL
- Mole, SE
- Fedichev, PO
Grupos
Abstract
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7( increment ex2) mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7( increment ex2) neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7( increment ex2) mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases. CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
Datos de la publicación
- ISSN/ISSNe:
- 2041-1723, 2041-1723
- Tipo:
- Article
- Páginas:
- -
NATURE COMMUNICATIONS NATURE PUBLISHING GROUP
Citas Recibidas en Web of Science: 14
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- No hay documentos
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Proyectos asociados
Red de Enfermedades Vasculares Cerebrales (INVICTUS PLUS)
Investigador Principal: Ángeles Almeida Parra
RD16/0019/0018 . Instituto de Salud Carlos III . 2017
3. Frailty and Aging. 3.1. Healthy aging biological mechanisms oriented to the maintenance of functional autonomy and mechanisms leading to frailty and disability. CICERFES
Investigador Principal: Juan Pedro Bolaños Hernández
CB16/10/00282 . Instituto de Salud Carlos III . 2017
Contrato Postdoctoral de Perfeccionamiento Sara Borrell
Investigador Principal: Juan Pedro Bolaños Hernández
CD18/00203 . Instituto de Salud Carlos III . 2019
Red Temática de Excelencia de Investigación en Hipoxia (RedHYPOX)
Investigador Principal: Ángeles Almeida Parra
SAF2017-90794-REDT . Ministerio de Ciencia, Innovación y Universidades . 2018
Cita
Lopez I,Garcia M,Buondelmonte C,Burmistrova O,Bonora N,Alonso P,Morant B,Vicente C,Jimenez D,Quintana R,Fernandez E,Llop J,Ramos P,Sharaireh A,Guevara M,Fitzpatrick L,Thompton CD,McKay TR,Storch S,Medina DL,Mole SE,Fedichev PO,Almeida A,Bolanos JP. Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis. Nat Commun. 2022. 13. (1):536. IF:16,600. (1).