Parkinson’s Disease (PD) is a devastating form of neurodegeneration that attacks patients’ motor skills, speech, and eventually mood, cognition and autonomic responses. The disease is characterized by a progressive loss of dopaminergic neurons from the brain region called the substantia nigra. These cells first accumulate large quantities of abnormally folded alpha-synuclein, and the disease is therefore considered an example of proteotoxicity.

What’s strange is that PD is so selective for a particular population of neurons. Alpha-synuclein is relatively widely expressed, so why are dopaminergic neurons singled out, while the rest of the brain remains (relatively) unscathed?

The answer (as well as an hint about why PD is usually a late-life disease), according to a new paper by Chan et al., may lie in an unusual form of calcium channel expressed in the adult form of these neurons. In adults, dopaminergic cells of the substantia nigra rely on the L-type Cav1.3 Ca2+ channel for pacemaking; in contrast, in young brains, these same cells use different types of calcium channels — the same sorts of channels used by neurons that aren’t susceptible to PD-induced cell death.

The authors also show that forcing adult dopaminergic neurons to adopt a more “youthful” type of calcium metabolism can protect these cells from the ravages of PD:

‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease

Why dopamine-containing neurons of the brain’s substantia nigra pars compacta die in Parkinson’s disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Cav1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson’s disease. These mechanisms remain latent in adulthood, and blocking Cav1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking (‘rejuvenation’) protects these neurons in both in vitro and in vivo models of Parkinson’s disease, pointing to a new strategy that could slow or stop the progression of the disease.

Note that rather than influencing channel expression via some sort of genetic manipulation, the authors use a pharmaceutical means of blocking the adult channel. Over time, the neurons revert to expression of the “youthful” calcium channel on their own.

I mention this explicitly because it means the findings are closer to a meaningful therapeutic form than if genetic manipulation had been used, or if the cells in question had to be removed from the brain for the intervention to take place: Too often we get good news that takes the form, “We cured the disease in culture! Now all we need to do is find a way to insert genes into cells behind the blood-brain barrier without giving the patient a cerebral hemorrhage, guaranteeing future brain cancer and lighting up the immune system like the Fourth of July,” or, “Once we know how to re-introduce modified neurons into the brain in a manner that allows them to form meaningful connections with existing circuits, we’ll have this problem licked.”

While I have every confidence that we’ll eventually figure out a way to safely implement gene therapy in the brain, it’s well outside our current capabilities. Whereas millions of people worldwide are suffering now, it’s nice to have some practically useful information to tide us over. Where there’s a small molecule — especially one of such exquisite specificity — there’s generally a way.