Pruning and loss of excitatory synapses by the parkin ubiquitin ligase.
Mutations in the PARK2 gene cause hereditary Parkinson disease (PD). The PARK2 gene product, termed parkin, is an E3 ubiquitin ligase that mediates the transfer of ubiquitin onto diverse substrate proteins. Despite progress in defining the molecular properties and substrates of parkin, little is known about its physiological function. Here, we show that parkin regulates the function and stability of excitatory glutamatergic synapses. Postsynaptic expression of parkin dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses onto hippocampal neurons. Conversely, knockdown of endogenous parkin or expression of PD-linked parkin mutants profoundly enhances synaptic efficacy and triggers a proliferation of glutamatergic synapses. This proliferation is associated with increased vulnerability to synaptic excitotoxicity. Thus, parkin negatively regulates the number and strength of excitatory synapses. Increased excitatory drive produced by disruption of parkin may contribute to the pathophysiology of PD.
Helton
Thomas D
TD
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Otsuka
Takeshi
T
Lee
Ming-Chia
MC
Mu
Yuanyue
Y
Ehlers
Michael D
MD
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D009154:Mutation; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009498:Neurotoxins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D051381:Rats; D013569:Synapses / Q000201:enzymology* / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
D009498:Neurotoxins; D018698:Glutamic Acid; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein