Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity.
Cerebellar atrophy
Inositol polyphosphate-4-phosphatase type I
Mouse model
Neurodegeneration
Pain-induced epilepsy
Phosphoinositide
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 07 2023
01 07 2023
Historique:
received:
06
03
2023
accepted:
27
06
2023
medline:
31
7
2023
pubmed:
7
7
2023
entrez:
7
7
2023
Statut:
ppublish
Résumé
Phosphoinositides (PIPs) act as intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism cause various pathological conditions, including neurodegenerative diseases, cancer and immune disorders. Several neurological diseases with diverse phenotypes, such as ataxia with cerebellar atrophy or intellectual disability without brain malformation, are caused by mutations in INPP4A, which encodes a phosphoinositide phosphatase. We examined two strains of Inpp4a mutant mice with distinct cerebellar phenotypes: the Inpp4aΔEx1,2 mutant exhibited striatal degeneration without cerebellar atrophy, and the Inpp4aΔEx23 mutant exhibited a severe striatal phenotype with cerebellar atrophy. Both strains exhibited reduced expression of Inpp4a mutant proteins in the cerebellum. N-terminal-truncated Inpp4a proteins were expressed from the Inpp4aΔEx1,2 allele by alternative translation initiation and had phosphatase activity for PI(3,4)P2, whereas the Inpp4a mutant protein encoded by Inpp4aΔEx23 completely lacked phosphatase activity. Our results indicate that the diverse phenotypes observed in Inpp4a-related neurological diseases could be due to the varying protein expression levels and retained phosphatase activity in different Inpp4a variants. These findings provide insights into the role of INPP4A mutations in disease pathogenesis and may help to develop personalized therapy.
Identifiants
pubmed: 37415561
pii: 323181
doi: 10.1242/dmm.050169
pmc: PMC10399444
pii:
doi:
Substances chimiques
Phosphoric Monoester Hydrolases
EC 3.1.3.2
phosphatidylinositol-3,4-bisphosphate 4-phosphatase
EC 3.1.3.66
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
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