Erik Nguyen Nielsen

Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Gottingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-alpha-[C-11]dihydrotetrabenazine ([C-11]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 mu g lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD.

Original languageEnglish
JournalExperimental Neurology
Volume303
Pages (from-to)142-152
Number of pages11
ISSN0014-4886
DOIs
Publication statusPublished - May 2018

    Research areas

  • Lactacystin, Microglia, Minipig, PET imaging, Parkinson's disease, Proteasome inhibition, Vesicular monoamine transporter 2, RATS, ALPHA-SYNUCLEIN, LACTACYSTIN MODEL, SUBSTANTIA-NIGRA, INCLUSION-BODIES, POSITRON-EMISSION-TOMOGRAPHY, VESICULAR MONOAMINE TRANSPORTER, IN-VIVO, NEURON DEGENERATION, PARKINSONS-DISEASE

See relations at Aarhus University Citationformats

ID: 121447456