Mitochondria and inflammation in Parkinson’s
Original article: Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson’s disease, European Journal of Neuroscience: November 8, 2018.
Studies using reprogrammed adult skin cells yield insights into specific pathways to Parkinson’s, originating in mitochondria and oxidative stress, which could be potentially targeted by a range of as yet untested compounds.
Why is it important?
The review identifies specific disease mechanisms and drug candidates with the potential for disease modification.
In order to survive and function, neurons need a reliable and adequate supply of energy, ways of disposing of dysfunctional cellular machinery and ultimately reducing oxidative stress: this can be thought of as “pollution” inside cells, which is the byproduct of normal processes. Mitochondria produce energy in neurons through a series of complex reactions, which when deranged can lead to excessive, and thus harmful, oxidative stress.
This review focuses on the body of evidence on mitochondrial dysfunction and oxidative stress in Parkinson’s, from a particular source of experiments using induced pluripotent stem cells (iPSCs). These are cells originally derived from reprogrammed adult skin cells, in this case from people with Parkinson’s who carry particular genetic mutations. iPSCs are useful for the purposes of experimentation on mitochondrial dynamics and studying oxidative stress because they also carry accumulated genetic changes as a result of ageing, which is thought to be a critical factor in Parkinson’s.
The authors review a range of studies using iPSCs carrying mutations in different genes. Mutations in SNCA, the gene for alpha synuclein, one of the most important pathological hallmarks of Parkinson’s, are associated with familial, early onset Parkinson’s. LRRK2 is also associated with familial Parkinson’s, and codes for enzymes which modify many proteins in cells. PINK1 and Parkin/PARK2 are genes involved in controlling the function of mitochondria and degrading damaged ones appropriately. PARK2 mutations are the most common cause of early onset familial Parkinson’s. Mutations in the GBA gene cause problems in handling lipids inside the cell which are necessary for the formation of membranes and neurotransmission; they are the most common genetic risk factor for Parkinson’s. In all these iPSC models, subtly different evidence of mitochondrial dysfunction and abnormal alpha synuclein accumulation has been reported. The mitochondrial changes may refer to mitochondrial volume, number and function. Many of these models also show elevated markers of oxidative stress which ultimately reduce neuron survival and can be traced to specific, but diverse, biochemical processes taking place inside mitochondria or on their outer surface. One of these for example involves cardiolipin (see earlier summary on PM).
All this evidence informs the search for disease modifying therapeutics which can target mitochondrial dynamics and aim to reduce oxidative stress: this was the rationale behind Phase III trials of Coenzyme Q10, for example, which unfortunately did not deliver positive results in a reasonably large group of people with Parkinson’s. However, other compounds which target mitochondria and reduce oxidative stress are promising and represent candidates worthy of consideration for trials: the authors review evidence for pioglitazone, nicotinamide riboside (NAD), kinetin, MAOB inhibitors, the antioxidant Honokiol and a particular kind of fatty acid.
As evidence accumulates, the case for each of these compounds eventually may mature so that some or all of these may be taken into trials soon. Watch this space!
Original article: Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson’s disease, European Journal of Neuroscience: November 8, 2018. Bose, A, Beal, MF.