Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells
Pišlar, Anja (Author), Zidar, Nace (Author), Kikelj, Danijel (Author), Kos, Janko (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0028390813003584 This link opens in a new window

The cysteine carboxypeptidase cathepsin X is an important player in degenerative processes under normal ageing and pathological conditions. In the present study, we investigated the potential role of cathepsin X in 6-hydroxydopamine (6-OHDA)-induced toxicity in the pheochromocytoma cell line PC12 and neuroblastoma cell line SH-SY5Y. Cells exposed to 6-OHDA demonstrated alterations in the protein level of cathepsin X and activity of cathepsin X. Down regulation of cathepsin X expression by siRNA attenuated the neuronal death caused by 6-OHDA. Treatment with specific cathepsin X inhibitor AMS36 protected cells against 6-OHDA mediated cytotoxicity, resulting in reduced cell death and apoptosis. Furthermore, AMS36 reversed 6-OHDA-induced loss of tyrosine hydroxylase and attenuated 6-OHDA-induced activation of caspase-3, triggering apoptosis, intracellular generation of reactive oxygen species and mitochondrial dysfunction, including the release of cytochrome c and an imbalanced Bax/Bcl-2 ratio. Moreover, AMS36 interfered with NF-kB activation by blocking degradation of IkB[alpha], preventing NF-kB translocation to the nucleus. Our data provide the first evidence that inhibition of cathepsin X protects both, PC12 and SH-SY5Y cells against 6-OHDA toxicity and indicate that cathepsin X may be responsible for dopamine neuron death, involved in the pathogenic cascade event for the neurodegenerative disorders, such as Parkinson's disease.

Keywords:cathepsin X, 6-hydroxydopamine, apoptosis, mitochondrial dysfunction, neuroprotection
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:str. 121-131
Numbering:Vol. 82
ISSN on article:0028-3908
DOI:10.1016/j.neuropharm.2013.07.040 Link is opened in a new window
COBISS.SI-ID:3499889 Link is opened in a new window
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Shortened title:Neuropharmacology
Publisher:Pergamon Press.
COBISS.SI-ID:278295 This link opens in a new window

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