Premium
Proteasomal inhibition leads to formation of ubiquitin/α‐synuclein‐immunoreactive inclusions in PC12 cells
Author(s) -
Rideout Hardy J.,
Larsen Kristin E.,
Sulzer David,
Stefanis Leonidas
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00474.x
Subject(s) - lactacystin , programmed cell death , ubiquitin , lewy body , cytoplasmic inclusion , proteasome , inclusion bodies , microbiology and biotechnology , cytoplasm , apoptosis , alpha synuclein , biology , pathogenesis , dopaminergic , autophagy , in vitro , synucleinopathies , parkinson's disease , proteasome inhibitor , disease , neuroscience , pathology , immunology , medicine , dopamine , biochemistry , escherichia coli , gene
Proteasomal dysfunction has been recently implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease and diffuse Lewy body disease. We have developed an in vitro model of proteasomal dysfunction by applying pharmacological inhibitors of the proteasome, lactacystin or ZIE[O‐ t Bu]‐A‐leucinal (PSI), to dopaminergic PC12 cells. Proteasomal inhibition caused a dose‐dependent increase in death of both naive and neuronally differentiated PC12 cells, which could be prevented by caspase inhibition or CPT‐cAMP. A percentage of the surviving cells contained discrete cytoplasmic ubiquitinated inclusions, some of which also contained synuclein‐1, the rat homologue of human α‐synuclein. However the total level of synuclein‐1 was not altered by proteasomal inhibition. The ubiquitinated inclusions were present only within surviving cells, and their number was increased if cell death was prevented. We have thus replicated, in this model system, the two cardinal pathological features of Lewy body diseases, neuronal death and the formation of cytoplasmic ubiquitinated inclusions. Our findings suggest that inclusion body formation and cell death may be dissociated from one another.