Deficiency of the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while higher levels are linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A loss or gain of function in these disorders are still not well understood, and treatments are still lacking. Here, using the Ube3a maternal loss (Ube3am-/p+) mouse model, we report an important JNK signaling activation in the hippocampus, cortex and cerebellum correlating with the onset of behavioral defects and biochemical marker alterations in the post-synaptic element, suggesting important spine pathology. JNK activation occurs at 7 and persists up till 23 weeks in Ube3am-/p+ mice in two different cellular compartments: the nucleus and the post-synaptic protein-enriched fraction. To study JNK's role in Ube3am-/p+ pathology we treated mice with the specific JNK inhibitor peptide, D-JNKI1, from 7 to 23 weeks of age. Preventing JNK action in vivo restores the post-synaptic protein-enriched fraction defects and the cognitive impairment in these mice. Our results imply a critical role of UBE3A-JNK signaling in the pathogenesis of UBE3A-related disorders. In particular, it was clear that JNK is a key player in regulating AS synaptic alterations and the correlated cognitive impairments, in fact, its specific inhibition tackles Ube3am-/p+ pathology. This study sheds new light on the neuronal functions of UBE3A and offers new prospects for understanding the pathogenesis of UBE3A-related disorders.
JNK signaling activation in the Ube3a maternal deficient mouse model: Its specific inhibition prevents post-synaptic protein-enriched fraction alterations and cognitive deficits in Angelman Syndrome model / C.A. Musi, G. Agrò, L. Buccarello, S. Camuso, T. BORSELLO. - In: NEUROBIOLOGY OF DISEASE. - ISSN 1095-953X. - 140(2020), pp. 104812.1-104812.12.
|Titolo:||JNK signaling activation in the Ube3a maternal deficient mouse model: Its specific inhibition prevents post-synaptic protein-enriched fraction alterations and cognitive deficits in Angelman Syndrome model|
MUSI, CLARA ALICE (Primo)
BORSELLO, TIZIANA (Ultimo) (Corresponding)
|Parole Chiave:||C-Jun-N-terminal-kinase; D-JNKI1; MAP-kinase stress pathway; Neurodevelopmental disease; Neuroprotection; Synaptic dysfunction|
|Settore Scientifico Disciplinare:||Settore BIO/16 - Anatomia Umana|
|Data di pubblicazione:||2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.nbd.2020.104812|
|Appare nelle tipologie:||01 - Articolo su periodico|