CMT 4B1: The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and main

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J Neurosci. 2010 Apr 21;30(16):5508-18

The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains

excitatory synapses by modulating endosomal traffic.

Lee HW, Kim Y, Han K, Kim H, Kim E.

National Creative Research Initiative Center for Synaptogenesis and Department

of Biological Sciences, Korea Advanced Institute of Science and Technology,

Daejeon 305-701, Korea.

Abstract

MTMR2 is a 3-phosphatase specific for the phosphoinositides PI(3)P and

PI(3,5)P(2), which are mainly present on endosomes. Mutations in the MTMR2 gene

in Schwann cells lead to a severe demyelinating peripheral neuropathy known as

Charcot-Marie-Tooth disease type 4B1.

MTMR2 expression is also detected in peripheral and central neurons, but neural

functions of MTMR2 remain unclear. Here, we report that MTMR2 is localized to

excitatory synapses of central neurons via direct interaction with PSD-95, a

postsynaptic scaffolding protein abundant at excitatory synapses.

Knockdown of MTMR2 in cultured neurons markedly reduces excitatory synapse

density and function. This effect is rescued by wild-type MTMR2 but not by a

mutant MTMR2 lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown

leads to a decrease in the intensity of EEA1-positive early endosomes in

dendrites but increases the intensity in the cell body region. Moreover, MTMR2

suppression promotes endocytosis, but not recycling, of the GluR2 subunit of

AMPA receptors, which is an endosomal cargo.

In addition, colocalization of internalized GluR2 with Lamp1-positive late

endosomes/lysosomes is enhanced in the cell body area but not in dendrites.

These results suggest that PSD-95-interacting MTMR2 contributes to the

maintenance of excitatory synapses by inhibiting excessive endosome formation

and destructive endosomal traffic to lysosomes.