VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation

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Abstract

BACKGROUND: Vacuolar protein sorting 35 (VPS35), a key component of retromer, plays an important role in endosome-to-Golgi retrieval of membrane proteins. Dysfunction of VPS35/retromer is a risk factor for neurodegenerative disorders, including AD (Alzheimer's disease) and PD (Parkinson's disease). However, exactly how VPS35-deficiency contributes to AD or PD pathogenesis remains poorly understood.<br /><br />RESULTS: We found that VPS35-deficiency impaired dendritic spine maturation and decreased glutamatergic transmission. AMPA receptors, GluA1 and GluA2, are significantly reduced in purified synaptosomal and PSD fractions from VPS35-deficient brain. The surface levels of AMPA receptors are also decreased in VPS35-deficient neurons. Additionally, VPS35 interacted with AMPA-type receptors, GluA1 and GluA2. Overexpression of GluA2, but not GluA1, could partially restore the spine maturation deficit in VPS35-deficient neurons.<br /><br />CONCLUSIONS: These results provide evidence for VPS35's function in promoting spine maturation, which is likely through increasing AMPA receptor targeting to the postsynaptic membrane. Perturbation of such a VPS35/retromer function may contribute to the impaired glutamatergic transmission and pathogenesis of neurodegenerative disorders, such as AD and PD.

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Tian, Y., Tang, F. L., Sun, X. D., Wen, L., Mei, L., Tang, B. S., & Xiong, W. C. (2015). VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation. Molecular Brain, 8(1). https://doi.org/10.1186/s13041-015-0156-4

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