TY - JOUR
T1 - Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells
AU - Fornai, Francesco
AU - Lenzi, Paola
AU - Gesi, Marco
AU - Soldani, Paola
AU - Ferrucci, Michela
AU - Lazzeri, Gloria
AU - Capobianco, Loredana
AU - Battaglia, Giuseppe
AU - De Blasi, Antonio
AU - Nicoletti, Ferdinando
AU - Paparelli, Antonio
PY - 2004/1
Y1 - 2004/1
N2 - Mice treated with the psychostimulant methamphetamine (MA) showed the appearance of intracellular inclusions in the nucleus of medium sized striatal neurones and cytoplasm of neurones of the substantia nigra pars compacta but not in the frontal cortex. All inclusions contained ubiquitin, the ubiquitin activating enzyme (E1), the ubiquitin protein ligase (E3-like, parkin), low and high molecular weight heat shock proteins (HSP 40 and HSP 70). Inclusions found in nigral neurones stained for α-synuclein, a proteic hallmark of Lewy bodies that are frequently observed in Parkinson's disease and other degenerative disorders. However, differing from classic Lewy bodies, MA-induced neuronal inclusions appeared as multilamellar bodies resembling autophagic granules. Methamphetamine reproduced this effect in cultured PC12 cells, which offered the advantage of a simple cellular model for the study of the molecular determinants of neuronal inclusions. PC12 inclusions, similar to those observed in nigral neurones, were exclusively localized in the cytoplasm and stained for α-synuclein. Time-dependent experiments showed that inclusions underwent a progressive fusion of the external membranes and developed an electrodense core. Inhibition of dopamine synthesis by α-methyl-p-tyrosine (αMpT), or administering the antioxidant S-apomorphine largely attenuated the formation of inclusions in PC12 cells exposed to MA. Inclusions were again observed when αMpT-treated cells were loaded with L-DOPA, which restored intracellular dopamine levels.
AB - Mice treated with the psychostimulant methamphetamine (MA) showed the appearance of intracellular inclusions in the nucleus of medium sized striatal neurones and cytoplasm of neurones of the substantia nigra pars compacta but not in the frontal cortex. All inclusions contained ubiquitin, the ubiquitin activating enzyme (E1), the ubiquitin protein ligase (E3-like, parkin), low and high molecular weight heat shock proteins (HSP 40 and HSP 70). Inclusions found in nigral neurones stained for α-synuclein, a proteic hallmark of Lewy bodies that are frequently observed in Parkinson's disease and other degenerative disorders. However, differing from classic Lewy bodies, MA-induced neuronal inclusions appeared as multilamellar bodies resembling autophagic granules. Methamphetamine reproduced this effect in cultured PC12 cells, which offered the advantage of a simple cellular model for the study of the molecular determinants of neuronal inclusions. PC12 inclusions, similar to those observed in nigral neurones, were exclusively localized in the cytoplasm and stained for α-synuclein. Time-dependent experiments showed that inclusions underwent a progressive fusion of the external membranes and developed an electrodense core. Inhibition of dopamine synthesis by α-methyl-p-tyrosine (αMpT), or administering the antioxidant S-apomorphine largely attenuated the formation of inclusions in PC12 cells exposed to MA. Inclusions were again observed when αMpT-treated cells were loaded with L-DOPA, which restored intracellular dopamine levels.
KW - α-synuclein
KW - Methamphetamine
KW - Neuronal inclusions
KW - Parkin
KW - Proteasome
KW - Ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=9144271094&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9144271094&partnerID=8YFLogxK
M3 - Article
C2 - 14675155
AN - SCOPUS:9144271094
VL - 88
SP - 114
EP - 123
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -