Abstract
Parkinson’s disease is the most common neurodegenerative disorder after Alzheimer’s disease, with the majority of cases being sporadic or “idiopathic”. The aetiology of the sporadic form is still unknown, but there is a broad consensus that Parkinson’s disease involves multiple pathways. In previous human post-mortem studies investigating substantia nigra of parkinsonian subjects, gene expression alterations in various metabolic pathways including protein folding, trafficking, aggregation, ubiquitination and oxidative stress were found. These studies revealed transcriptomic dysregulation of various genes, amongst others Skp1A and PSMC4 (part of ubiquitin-proteasome system), HSC70 (belonging to the chaperone family) and ALDH1A1 (an enzyme involved in the catabolism of dopamine). To investigate whether these alterations are manifested at the protein level, we performed immunohistochemical analysis in the substantia nigra of Parkinson’s disease and compared them to Alzheimer’s disease and non-neurological post-mortem controls. We were able to confirm cell-specific reductions in the protein content of ALHD1A1 and Skp1A in the dopaminergic neurons of the substantia nigra of Parkinsonian patients compared to Alzheimer’s and control subjects. Furthermore, we observed particular distribution for HSC70 and PSMC4 in the cytoplasm and accumulation within Lewy body in the dopaminergic neurons of the substantia nigra in Parkinson patients. These findings, together with previous evidence, suggest a malfunction of the ubiquitin-proteasome and possible autophagy systems as major players in protein misfolding and aggregation in Parkinson’s disease. Nevertheless, this needs further proof, possibly with trajectory time line.
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Acknowledgments
We thank the tissue donors and their families, the Department of Neuropathology, University of Würzburg, Germany (member of the BrainNet Europe-BNEII) and the Netherlands Brain Bank, for providing the post-mortem brain samples. The authors acknowledge the financial support from the Technion Research and Development Authorities and the Eve Topf Center of Excellence. The authors would like to acknowledge Dr. Jasmin Bartl for her assistance with the Olympus CellP software programming, Ms. Vinita Jagannath for statistical support and to Mrs. Michaela Hartmann, Mrs. Hannelore Schraut and Dr. Irina Reiter for their technical work supporting this research. We thank Philip Thwaites for his advice in English editing.
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EG, PR, MBHY and SAM contributed to the conception and designed of the work.
EG, CMM and SAM contributed to the acquisition of the data for the work.
EG and JR contributed to analysis and drafting of the data and work.
EG, JR, PR and SAM contributed to the interpretation of the data.
EG, JR, CMM, PR, MBHY, and SAM contributed to the critical revision and approval of the final version of the manuscript.
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The brain samples used in this study were supplied by Brain Net Europe (BNEII) and the Netherlands Brain bank. The entire procedure was performed in accordance with the Helsinki Declaration in its latest version and with the Convention of the Council of Europe on Human Rights and Biomedicine. Informed written consent for tissue donation was obtained from the individuals or the next of kin. Local ethic permission working with post-mortem material was received from the University of Würzburg (Study No. 78/99).
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Grünblatt, E., Ruder, J., Monoranu, C.M. et al. Differential Alterations in Metabolism and Proteolysis-Related Proteins in Human Parkinson’s Disease Substantia Nigra. Neurotox Res 33, 560–568 (2018). https://doi.org/10.1007/s12640-017-9843-5
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DOI: https://doi.org/10.1007/s12640-017-9843-5