Listed in Issue 293


LA COGNATA  and COLLEAGUES, 1 Section of Human Anatomy and Histology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 2 Institute of Neurological Sciences, National Research Council, Catania, Italy; 3 Department of Human Science and Promotion of Quality of Life, San Raffaele Open University of Rome, Rome, Italy; 4 Section of Animal Biology, Department of Biological, Geological, and Environmental Sciences, University of Catania, Catania, Italy explored the role of parkin proteins in PD neurodegeneration for the first time by analyzing their expression profile in an in vitro model of PD.


Mutations in PARK2 (or parkin) are responsible for 50% of cases of autosomal-recessive juvenile-onset Parkinson's disease (PD). To date, 21 alternative splice variants of the human gene have been cloned.


Yet most studies have focused on the full-length protein, whereas the spectrum of the parkin isoforms expressed in PD has never been investigated. In this study, the role of parkin proteins in PD neurodegeneration was explored for the first time by analyzing their expression profile in an in vitro model of PD. To do so, undifferentiated and all-trans-retinoic-acid (RA)-differentiated SH-SY5Y cells (which thereby acquire a PD-like phenotype) were exposed to PD-mimicking neurotoxins: 1-methyl-4-phenylpyridinium (MPP+ ) and 6-hydroxydopamine (6-OHDA) are widely used in PD models, whereas carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and carbobenzoxy-Leu-Leu-leucinal (MG132) interfere, respectively, with mitochondrial mitophagy and proteasomal degradation.


Following treatment with each neurotoxin H1, the first parkin isoform to be cloned, was down-regulated compared to the respective controls both in undifferentiated and RA-differentiated cells. In contrast, the expression pattern of the minor splice isoforms varied as a function of the compound used: it was largely unchanged in both cell cultures (eg, H21-H6, H12, XP isoform) or it showed virtually opposite alterations in undifferentiated and RA-differentiated cells (eg, H20 and H3 isoform).


This complex picture suggests that up- or down-regulation may be a direct effect of toxin exposure, and that the different isoforms may exert different actions in neurodegeneration via modulation of different molecular pathways.


Valentina La Cognata  1   2 , Grazia Maugeri  1 , Agata Grazia D'Amico  1   3 , Salvatore Saccone  4 , Concetta Federico  4 , Sebastiano Cavallaro  2 , Velia D'Agata  1. Differential expression of PARK2 splice isoforms in an in vitro model of dopaminergic-like neurons exposed to toxic insults mimicking Parkinson's disease. J Cell Biochem. ;119(1):1062-1073. doi: 10.1002/jcb.26274. Epub Aug 23 2017 . 2018 Jan.

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