Shedding light on early Parkinson's disease pathology

"The most intriguing finding of our study was the lack of a significant decrease of TH levels in the SN of the low-dose MPTP-treated mice, suggesting that this treatment does not induce a direct loss of nigral dopaminergic neurons," says Joost Verhaagen PhD, lead investigator of the study. "These findings appear to support the 'dying back' hypothesis of PD, which proposes that the TH-positive terminal loss in the striatum is the first neurodegenerative event in PD, which later induces neuronal degeneration in the SN." Dr. Verhaagen is Head of the Workgroup on Neuroregeneration at the Netherlands Institute for Neuroscience and Professor at the Free University in Amsterdam.

The neurotoxin MPTP (1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine) was used to induce the degenerative changes. Chronic 5 week administration of 25 mg/kg MPTP combined with probenecid (250 mg/kg), which inhibits MPTP clearance and promotes its crossing of the blood-brain barrier, is known to cause dopaminergic neuron degeneration in the SN and decrease striatal dopaminergic nerve terminals. In the current study, 7 mice were treated with 25 mg/kg MPTP plus probenecid, 6 mice received a lower dose of MPTP (15 mg/kg) plus probenecid, and 8 control mice received saline plus probenecid. A grid test, known to be sensitive to striatal dopaminergic input, was used to detect motor deficits.

Immunohistochemical analysis using TH fluorescence revealed that only the higher dose of MPTP produced significant dopaminergic neuronal cell loss in the SN (65% fluorescence loss, p<0.001). The 15 mg/kg dose produced an 18% decline in fluorescence which was not significantly different than control.

Both dose levels significantly reduced TH immunoreactivity of the striatum. The authors believe that the motor deficits seen at both MPTP dose levels relate to the striatal dopamine depletion.

The study is also the first to report that low-dose MPTP produces astrogliosis and microgliosis in the SN and formation of α-synuclein positive inclusions. "The data suggests that gliosis in the substantia nigra plays a prominent initiating role in the introduction of dopaminergic deficits after MPTP treatment, and may be sufficient to significantly reduce TH levels in the striatum," says Dr. Korecka, first author and principal investigator of the study and a post-doctoral fellow at the Netherlands Institute for Neuroscience in Amsterdam.

"We are the first to report that this early PD model provides an interesting window of opportunity to study the mechanisms that underlie the early neurodegenerative events that initiate the cellular death of dopaminergic neurons," write the authors. They suggest that the model can be used to develop potential treatment strategies to counteract early PD cellular changes.