Abstract
BackgroundParkinson’s disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could contribute to the etiology of PD by disrupting excitatory neurotransmission. Here, we evaluate the impact of four common PD-associated Parkin point mutations (T240M, R275W, R334C, G430D) on glutamatergic synaptic function in hippocampal neurons.ResultsWe find that expression of these point mutants in cultured hippocampal neurons from Parkin-deficient and Parkin-null backgrounds alters NMDA and AMPA receptor-mediated currents and cell-surface levels and prevents the induction of long-term depression. Mechanistically, we demonstrate that Parkin regulates NMDA receptor trafficking through its ubiquitination of GluN1, and that all four mutants are impaired in this ubiquitinating activity. Furthermore, Parkin regulates synaptic AMPA receptor trafficking via its binding and retention of the postsynaptic scaffold Homer1, and all mutants are similarly impaired in this capacity.ConclusionOur findings demonstrate that pathogenic Parkin mutations disrupt glutamatergic synaptic transmission in hippocampal neurons by impeding NMDA and AMPA receptor trafficking. Such effects may contribute to the pathophysiology of PD in PARK2 patients.
Highlights
Parkinson’s disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could contribute to the etiology of PD by disrupting excitatory neurotransmission
Pathogenic Parkin mutations alter AMPA-type glutamate receptor (AMPAR) and NMDA receptor (NMDAR) cell-surface levels and currents More than 200 pathogenic mutations have been identified in PARK2, comprising point mutations, deletions, and exonic rearrangements that are associated with early-onset PD and autosomal recessive juvenile PD [5, 33, 34]
We previously showed that direct binding of Parkin to Homer1 is necessary for maintaining surface AMPAR levels, by tethering endocytic zones (EZs) for AMPAR capture and internalization to the postsynaptic density [19]
Summary
Parkinson’s disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could contribute to the etiology of PD by disrupting excitatory neurotransmission. PARK2 encodes Parkin, a RING-between-RING domain E3 ubiquitin ligase that catalyzes the covalent attachment of ubiquitin to specific substrates and regulates vital cellular processes including mitochondrial quality control and apoptosis [5,6,7]. It remains unclear how Parkin loss-of-function precipitates the death of midbrain dopaminergic neurons to cause PD, its ubiquitination of mitochondrial proteins downstream of the kinase PINK1 has been shown to mediate mitophagy, a selective form of autophagy [8,9,10,11].
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