Journal
BIOMOLECULES
Volume 12, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/biom12081108
Keywords
alpha synuclein; Parkinson's disease; SNCA duplication; nuclear alpha synuclein
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Funding
- Interdisciplinary Center for Clinical Research of the University Hospital Erlangen, Germany
- Bundesministerium fur Bildung und Forschung, Gernamy (BMBF) [01EK1605B]
- Fritz Thyssen Foundation [10.19.2.024MN]
- Marohn Foundation
- Medical Research Foundation, University Hospital Erlangen
- Deutsche Forschungsgemeinschaft
- Friedrich-Alexander-Universitat Erlangen-Nurnberg
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [270949263/GRK2162, WI 3567/2-1]
- Bavarian Research Consortia Induced Pluripotent Stem Cells (ForIPS)
- Bavarian Research Consortia Interaction of Human Brain Cells (ForInter)
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This study identified distinct nuclear and cytosolic species of aSyn and revealed their redistribution during neuronal differentiation. Furthermore, a different distribution pattern of aSyn was observed in cells from PD patients carrying aSyn gene duplication.
Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson's disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood. Current knowledge suggests the existence of various aSyn species with distinct structural and biochemical properties. Here, we identified a C-terminal-targeting aSyn antibody (Nu-aSyn-C), which has a high immunoaffinity towards aSyn in the nucleus. Comparing the Nu-aSyn-C antibody to aSyn antibodies developed against phosphorylated or aggregated forms, we observed that nuclear aSyn differs from cytosolic aSyn by an increased phosphorylation and assembly level in proliferating cells. Employing Nu-aSyn-C, we characterized aSyn distribution during neuronal differentiation in midbrain dopaminergic neurons (mDANs) derived from human-induced pluripotent stem cells (hiPSCs) and Lund human mesencephalic cells, and in primary rat hippocampal neurons. We detected a specific translocation pattern of aSyn during neuronal differentiation from the nucleus to the soma and finally to neuronal processes. Interestingly, a remarkable shift of Nu-aSyn-C-positive species towards neurites was detected in hiPSC mDANs from a PD patient carrying aSyn gene duplication. Together, our results reveal distinct nuclear and cytosolic aSyn species that redistribute during neuronal differentiation-a process that is altered in PD-derived neurons.
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