Abstract
Dysfunction of the ubiquitin-proteasome system occurs in the substantia nigra (SN) in Parkinson's disease (PD). However, it is unknown whether this is a primary cause or a secondary consequence of other components of the pathogenic process. We have investigated in nonhuman primates whether initiating cell death through mitochondrial complex I inhibition using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) altered proteasomal activity or the proteasomal components in the SN. Chymotrypsin-like, trypsin-like and peptidylglutamyl-peptide hydrolase (PGPH) activating of 20S proteasome were decreased in SN homogenates of MPTP-treated marmosets compared to naive animals. Western blotting revealed a marked decrease in the expression of 20S-alpha subunits, but no change in 20S-beta subunits in the SN of MPTP-treated marmoset compared to naive animals. There was a marked decrease in the expression of the proteasome activator 700 (PA700) and proteasome activator 28 (PA28) regulatory complexes. The 20S-alpha 4 subunit immunoreactivity was decreased in the nucleus of colocalized tyrosine hydroxylase (TH)-positive cells of MPTP-treated animals compared to naive animals but no difference in the intensity of 20S-beta 1i subunit staining. Immunoreactivity for PA700-Rpt5 and PA28-alpha subunits within surviving TH-positive cells of MPTP-treated marmoset was reduced compared to naive controls. Overall, the changes in proteasomal function and structure occurring follow MPTP-induced destruction of the SN in common marmosets were very similar to those found in PD. This suggests that altered proteasomal function in PD could be a consequence of other pathogenic processes occurring in SN as opposed to initiating cell death as previously suggested.
Original language | English |
---|---|
Pages (from-to) | 1766-1774 |
Number of pages | 9 |
Journal | European Journal of Neuroscience |
Volume | 23 |
Issue number | 7 |
DOIs | |
Publication status | Published - Apr 2006 |
Keywords
- common marmoset
- MPTP
- Parkinson's disease
- proteasome activity
- proteasome subunits
- ubiquitin-proteasome pathway
- SPORADIC PARKINSONS-DISEASE
- MITOCHONDRIAL COMPLEX-I
- OXIDIZED PROTEINS
- OXIDATIVE DAMAGE
- ALPHA-SYNUCLEIN
- 20S PROTEASOME
- ANTIGEN PRESENTATION
- INHIBITION CAUSES
- SUBSTANTIA-NIGRA
- LEWY BODIES