Parkinson’s disease is characterised by loss of dopaminergic neurons in the area of the midbrain known as the substantia nigra. Although mitochondrial stress – an accumulation of damaging superoxide and free radicals – is believed to be the cause of cell death, it is not understood why this subset of neurons is especially vulnerable.
Researchers at Northwestern University have now suggested a possible answer: these neurons have an inherently stressful ‘lifestyle’. The cells in the substantia nigra act as pacemakers, releasing rhythmic bursts of dopamine. This activity is accompanied by an influx of calcium ions which must then be pumped back out of the cell in an energy-demanding process. The inflow of calcium ions is not essential for pacemaking activity so, if the energy needed to pump calcium ions out of the cell is adding extra stress, blocking the influx of calcium should help to alleviate this. Using mice engineered to express a redox-sensitive fluorescent protein in their mitochondria, the team showed that the opening of L-type calcium channels during normal pacemaking activity created an oxidant stress that was specific to dopaminergic cells of the substantia nigra. The oxidative stress, in turn, caused a defensive mild mitochondrial depolarization or uncoupling.
Although most cases of Parkinson’s disease have no known genetic cause, loss-of-function DJ-1 (PARK7) mutations can cause early-onset Parkinson’s disease in humans and transgenic mice lacking DJ-1 also show damage to dopaminergic cells in the substantia nigra. Knocking out DJ-1 down-regulates expression of two uncoupling proteins and increases oxidation of mitochondrial matrix proteins in dopaminergic neurons of the substantia nigra. Treatment of the transgenic animals with the L-type calcium channel blocker, isradipine, was found to protect the dopaminergic cells of the substantia nigra from oxidative damage.
The study, which is published in the journal Nature, builds on previous studies linking calcium channel blockade with protective effects in Parkinson’s disease.
A clinical trial is currently underway to examine the safety, tolerability and efficacy of isradipine – which is already approved for the treatment of high blood pressure – in patients with Parkinson’s disease. The hope is that the drug will slow disease progression and allow a broader window for existing symptomatic treatments.