Rasopathy-Associated Mutation Ptpn11D61Y has Age-Dependent Effect on Synaptic Vesicle Recycling

. 2024 Nov 21 ; 44 (1) : 77. [epub] 20241121

Jazyk angličtina Země Nizozemsko Médium electronic

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid39570442

Grantová podpora
01GM1902B Bundesministerium für Bildung und Forschung
01GM1902B Bundesministerium für Bildung und Forschung
101080580 European Commission
101080580 European Commission

Odkazy

PubMed 39570442
PubMed Central PMC11582327
DOI 10.1007/s10571-024-01505-1
PII: 10.1007/s10571-024-01505-1
Knihovny.cz E-zdroje

Rasopathies are genetic disorders often associated with developmental delay and intellectual disability. Noonan syndrome (NS) is one of the most common Rasopathies, caused by mutations in PTPN11 in more than 50% of cases. In mammalian neurons, PTPN11 controls the trafficking of postsynaptic glutamate receptors. This process is disrupted in neurons expressing PTPN11 variants associated with Rasopathies and is thought to contribute to the cognitive impairments in Noonan syndrome. Recent work revealed presynaptic impairments upon expression of RASopathy-linked PTPN11 variants in Drosophila. However, the presynaptic role of PTPN11 has not yet been addressed in mammals. Here, we investigated membrane trafficking of synaptic vesicles in cultured mouse cortical neurons expressing Rasopathy-associated PTPN11D61Y variant. We observed a significantly smaller readily releasable and total recycling pool of synaptic vesicles. The drop in synaptic vesicle release competence was accompanied by a decreased rate of SV retrieval. Interestingly, the presynaptic phenotype was evident in mature (DIV21) but not in immature (DIV12) neurons. Thus, our data reveal importance of balanced PTPN11 activity for normal trafficking of neurotransmitter-filled synaptic vesicles in the presynaptic ending of mature neurons.

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