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The Journal of Neuroscience, September 1, 2000, 20(17):6365-6373

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

Philipp J. Kahle¹, Manuela Neumann², Laurence Ozmen³, Veronika Müller¹, Helmut Jacobsen³, Alice Schindzielorz¹, Masayasu Okochi¹, Uwe Leimer¹, Herman van der Putten⁴, Alphonse Probst⁵, Elisabeth Kremmer⁶, Hans A. Kretzschmar², and Christian Haass¹

¹ Adolf Butenandt Institute, Department of Biochemistry, Ludwig Maximilians University, 80336 Munich, Germany, ² Institute of Neuropathology, University of Göttingen, 37075 Göttingen, Germany, ³ Pharma Research, Gene Technology, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland, ⁴ Nervous System, Novartis Pharma Ltd., 4002 Basel, Switzerland, ⁵ Institute of Pathology, University of Basel, 4003 Basel, Switzerland, and ⁶ Gesellschaft für Strahlenschutzforschung Institute of Molecular Immunology, 81377 Munich, Germany

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

Key words: synuclein; synaptophysin; brain; synapse; Parkinson's disease; Lewy body

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20176365-09$05.00/0

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