Rewiring cellular metabolism: anti-diabetic drugs yield further potential for disease modification

Cellular metabolism and energy production are the central links between type II diabetes and Parkinson’s: common to both of these apparently disparate conditions are mitochondrial dysfunction and insulin resistance. Mitochondria generate energy for all cells in the human body except red blood cells, and insulin is essential in aiding the transport of carbohydrates, the major fuel for energy, into cells. When cells become desensitised to insulin, this process becomes dysregulated, and inflammation and other adverse consequences ensue.

Exenatide, an antidiabetic drug which targets the GLP1 receptor and has shown a number of neuroprotective effects in pre-clinical studies, was prioritised by the LCT Committee and two trials in people with Parkinson’s have so far been supported by The Cure Parkinson’s Trust (CPT). The latest trial made headlines with exciting results: compared to placebo, exenatide reduced the progression of motor symptoms. Crucially, these benefits were sustained a year later after treatment cessation, and a large multi-centre trial is now the essential next step.

A new line of research into another class of antidiabetic drugs, known as glitazones, is now placing their cellular target, the mitochondrial pyruvate carrier, or MPC, in the spotlight. Glitazones improve the cell’s sensitivity to insulin. Once in the cell, carbohydrates are broken down to a smaller molecule, pyruvate, which must be ferried into mitochondria where it can be broken down into fuel for metabolism. The MPC, which glitazones also target, is essential in this process, and numerous sources of evidence are now pointing to this as the next hot cellular target for disease modification in Parkinson’s. The side effects seen with glitazones however have prompted the development of drugs that target the MPC without impacting on the pathway responsible for their main adverse effects.

The novel drug in question, MSDC-0160, which is supported by extensive satisfactory studies in experimental animals, has also been prioritised by the LCT committee and preclinical work supported by CPT is now underway. It ameliorates the effects of toxins, and prevents cells from going into defensive overdrive when exposed to oxidative stress, which is known to damage neurons. It also appears to rewire metabolism, changing the way in which cells use alternative sources of fuel. Overall, this drug has been shown to reduce neuronal inflammation and promote their survival. One of the key ways in which MSDC-0160 appears to do this is by regulating autophagy, that is waste removal within the cell, which has been implicated in several different genetic variants of Parkinson’s including LRRK2 and GBA.

There are still many open questions around MSDC-0160 and the mechanism by which it appears to rewire metabolism is not yet fully understood. Many of its effects are seen in neurons, but also glial cells, which are 10 times more abundant in the brain and are central to neuronal inflammation. What effects might it have on non-motor symptoms, where inflammation appears to be important? Could it synergise with exenatide for fuller therapeutic benefit? These are important questions - watch this space!

Original article

Quansah, E., Peelaerts, W., Langston, J. W., Simon, D. K., Colca, J., & Brundin, P. (2018). Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration. Molecular Neurodegeneration, 13, 28-40.