MPTP treatment of common marmosets impairs proteasomal enzyme activity and decreases expression of structural and regulatory elements of the 26S proteasome

Bai-Yun Zeng, Mahmoud M. Iravani, S. T. Lin, M. Irifune, M. Kuoppamaki, G. Al-Barghouthy, L. Smith, M. J. Jackson, S. Rose, A.D. Medhurst, P. Jenner

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25 Citations (Scopus)

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 languageEnglish
Pages (from-to)1766-1774
Number of pages9
JournalEuropean Journal of Neuroscience
Volume23
Issue number7
DOIs
Publication statusPublished - 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

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