Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant α-Synuclein in Human and Transgenic Mouse Brain

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Mutations in the α-synuclein (αSYN) gene are associated with rare cases of familial Parkinson9s disease, and αSYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]αSYN as well as βSYN at the cellular and subcellular level. Our direct comparative study demonstrates extensive synaptic colocalization of αSYN and βSYN in human and mouse brain. In a sucrose gradient equilibrium centrifugation assay, a portion of βSYN floated into lower density fractions, which also contained the synaptic vesicle marker synaptophysin. Likewise, wild-type and [A30P]αSYN were found in floating fractions. Subcellular fractionation of mouse brain revealed that both αSYN and βSYN were present in synaptosomes. In contrast to synaptophysin, βSYN and αSYN were recovered from the soluble fraction upon lysis of the synaptosomes. Synaptic colocalization of αSYN and βSYN was directly visualized by confocal microscopy of double-stained human brain sections. The Parkinson9s disease-associated human mutant [A30P]αSYN was found to colocalize with βSYN and synaptophysin in synapses of transgenic mouse brain. However, in addition to their normal presynaptic localization, transgenic wild-type and [A30P]αSYN abnormally accumulated in neuronal cell bodies and neurites throughout the brain. Thus, mutant [A30P]αSYN does not fail to be transported to synapses, but its transgenic overexpression apparently leads to abnormal cellular accumulations.