Back in the '80s the name Michael J. Fox was more or less interchangeable with that of Marty McFly, the effortlessly cool protagonist from the Back to the Future trilogy who introduced an entire generation of kids to hoverboards, self-lacing shoes and flux capacitors. Not to mention 'Johnny B Goode'. These days however Fox's name is more likely to have us thinking of his fight with Parkinson's disease, which he was diagnosed with back in 1991, or the advocacy work he does for his aptly named Michael J. Fox Foundation for Parkinson's Research. Looking at their mission statement you can't help but get the feeling that Fox has brought a little of Marty "nobody calls me chicken" McFly's fighting spirit to the Foundation as it dedicates itself to "finding a cure for Parkinson's disease through an aggressively funded research agenda". Whilst a cure remains allusive, recent research funded by the Foundation has resulted in a giant leap forward in our understanding of Parkinson's disease and suggests that the cure which Fox hopes will one day put him out of business may not be as far off as once thought.
It all starts in the basal ganglia
Clinically, Parkinson's disease (PD) is characterised by an array of motor symptoms including tremors, rigidity, slowness of movement (or bradykinesia) and gait and walking difficulties. Symptoms which are thought to result from neuronal degeneration within the substantia nigra, a small region of the basal ganglia which acts to produce and release the neurotransmitter dopamine. The basal ganglia is a highly organised group of structures located at the base of the forebrain which exerts a constant inhibitory effect on our various motor systems. An effect which helps to prevent our bodies from becoming inappropriately active. And that's where dopamine comes in. The dopamine, produced by the substantia nigra, acts to facilitate the release of the basal ganglia's inhibitory influence, and thus allows movement to occur. It might be easier to think of the motor system as a somewhat fused set of gears attached to a small motor. Despite the motor (motor system) being active the friction (basal ganglia) is too great to allow the gears to turn. The friction can however be overcome by spraying a small amount of lubricant (our dopamine in this analogy) onto the gears, thus whilst the dopamine doesn't actively turn the gears it acts to reduce the constant friction between the gears thus allowing the motor to initiate movement. Our brains work in much the same way, everything is able to work smoothly in the presence of our personal lubricant, dopamine (sounds wrong I know but stick with me here), however when sufficient levels of dopamine are not available, such as in Parkinson's disease, our ability to initiate and control our movements slowly grinds to a halt.
Like most neurodegenerative conditions, the neuronal loss associated with Parkinson's disease occurs due to a variety of factors, some of which are environmental whilst others are genetic. However, as is often the case, it is the rarer genetic forms of the disease which offer the greatest promise for therapeutic advancement in the field. Approximately one in 10 Parkinson's cases result from mutations in the parkin gene, a gene on chromosome six which encodes a component of the E3 ubiquitin ligase complex (for those of you playing at home). Normally this knowledge would result in the use of a mouse model of the disease, however parkin knockout mice show no signs of Parkinson's disease suggesting that parkin mutations act selectively on human nigral dopaminergic neurons. The selective nature of the parkin gene was, until recently, a major hurdle in Parkinson's research as the complexity of neuronal networks in the human brain make it incredibly difficult to study the genetic form of the disease. After all parkin-affected dopaminergic human neurons aren't something you can just grow in a lab. Or at least they weren't, until now.
Test tube neurons
That's right for the first time ever scientists have managed to generate human dopaminergic neurons from Parkinson's disease patients with parkin mutations. And what's more they made them from skin. Ok so to be more specific the researchers generated human induced pluripotent stem cells from dermal fibroblasts (skin cells), collected from two Parkinson's patients (both with parkin mutations) and two controls. The stem cells were subsequently used to generate the dopaminergic neurons some of which contained the parkin mutations and some of which did not. The generation of these mutant neurons allowed the researchers to finally observe parkin in action in its native habitat, and enabled them to see just how mutations in the gene were leading to neuronal damage. As it would turn out normal parkin acts to control the production of monoamine oxidase, or MAO for short, an enzyme which acts to catalyse dopamine oxidation. The production of MAO is normally tightly controlled to ensure that adequate levels of dopamine are being oxidised and our movements are able to all run smoothly. However when parkin mutations occur, the tight control of MAO production is lost and MAO is expressed at much higher levels. But what's the big deal? Surely there's nothing wrong with a bit of extra MAO floating around the place. After all it just means we'll have some MAO for a rainy day, right? Wrong. As it would happen MAO production is generally tightly controlled for a very good reason. It's toxic! Yep, at high levels MAO leads to the degeneration of our dopaminergic neurons as a result of oxidative stress. And no amount of shiraz-based anti-oxidants can do anything about it. But whilst shiraz may not work, it turns out that restoring control over MAO production does, as lead author Houbo Jiang and his team found that the early-stage damage could be reversed by delivering normal parkin back into the cells.
As well as providing insight into the role parkin plays in genetic forms of the disease, these findings also provide a novel target for future Parkinson's treatments. MAO production. Whilst one of the drugs currently on the market acts to inhibit MAO activity, there are no therapies which attempt to restore control over MAO production. At least not for the time being. So with the hope these findings seem to be injecting into the field of Parkinson's research, you can't help but get the feeling that if Marty McFly were reading this now he'd smile and say 'if only they knew, there's just a few short years to go'. And I for one am hoping he's right.
- Jiang, H., Ren, Y., Yuen, E., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., Yan, Z., & Feng, J. (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells Nature Communications, 3 DOI: 10.1038/ncomms1669
- Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, Blesa FJ, Guridi J, Marin C, & Rodriguez M (2008). Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society, 23 Suppl 3 PMID: 18781672