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.
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