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Fabrizio Gardoni "MAGUK proteins: New targets for pharmacological intervention in the glutamatergic synapse"

Abstract :

The PSD-95-like subfamily of MAGUKs (PSD-MAGUKs), including also PSD-93, SAP-102 and SAP-97, organizes ionotropic glutamate receptors and their associated signalling proteins in the postsynaptic density (PSD) of the excitatory synapse regulating the strength of synaptic activity.
Of relevance, modifications of PSD-MAGUKs function have been recently described in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In addition, a role of PSD-MAGUK proteins in other neurological disorders such as ischemia has been recently put forward. In particular, modifications of PSD-MAGUK proteins interactions with NMDA receptors regulatory subunits are a common event in all these disorders. On this view, a better knowledge and understanding of PSD-MAGUKs function as well as of the molecular events regulating PSD-MAGUK-mediated interactions in the glutamatergic synapse could lead to the identification of new pharmaceutical targets for the therapy of CNS disorders.
Here I will present a model of early Parkinson’s Disease in which partial denervation causing mild motor deficits selectively affects Long Term Potentiation and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that Dopamine lowering influence corticostriatal synaptic plasticity depending upon the level of depletion. The use of the TAT2A cell-permeable peptide, as an innovative therapeutic strategy in early PD able to reduce NR2A interaction with PSD-MAGUK proteins, rescues physiological NMDA receptor composition, synaptic plasticity and motor behavior.
Further, we have recently reported that SAP97 is also capable of driving ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for alpha-secretase) to the post synaptic membrane by direct interaction. This interaction can be disrupted by a cell-permeable peptide, Tat-Pro ADAM709-729, that mimics the proline-rich region of ADAM10, responsible for its association to SAP97. Here we administered this peptide in vivo in mice for 14 days. The disruption of SAP97/ADAM10 interaction reduces ADAM10 trafficking towards the membrane as well as ADAM10-mediated non-amiloidogenic cleavage of Amyloid Precursor Protein (APP), reduces the release of solubleAPPalpha, one of the products of ADAM10 cleavage, and of the ratio between APP-CTF83 and APP-CTF99. Since AD is characterized by synaptic dysfunction, we investigated biochemically the effects of the reduction of ADAM10 activity for 14 days on the molecular composition of the glutamatergic synapse. Interestingly, peptide treatment induce also a disturbance of the structural organization of the post synaptic compartment of the glutamatergic synapse is evident, involving primarily a shifting in the composition of synaptic NR2A containing NMDA receptors. This reduction is associated with an impairment in NMDA-dependent LTP in hippocampal slices of mice treated with the peptide. Our findings indicate that the decrease of APP physiological metabolism can affect the molecular composition of the postsynaptic compartment of the glutamatergic synapse leading to alterations of synaptic function.

Selected publications

MAGUK proteins: New targets for pharmacological intervention in the glutamatergic synapse.
Eur J Pharmacol. 2008 May 6;585(1):147-52. Epub 2008 Feb 26.
Marcello E, Epis R, Gardoni F, Di Luca M.
The amyloid cascade: the old and the new.
J Nutr Health Aging. 2008 Jan;12(1):58S-60S. Review.
Gardoni F, Frasca A, Zianni E, Riva MA, Di Luca M, Fumagalli F. Repeated treatment with haloperidol, but not olanzapine, alters synaptic NMDA receptor composition in rat striatum. Eur Neuropsychopharmacol. 2008 Jul;18(7):531-4.

Borroni B, Gardoni F, Parnetti L, Magno L, Malinverno M, Saggese E, Calabresi P, Spillantini MG, Padovani A, Di Luca M.
Pattern of Tau forms in CSF is altered in progressive supranuclear palsy.
Neurobiol Aging. 2007 Aug 18. [Epub ahead of print]
PMID: 17709155 [PubMed - as supplied by publisher]

Laurent Groc