MAPK: The Regulator Of Disease?

Alzheimer’s disease, Parkinson’s disease and Lou Gehrig’s disease. What do these three diseases have in common? Well, according to recent research, all three may be caused by the MAPK pathway. In order to understand these similarities however we must define a few things. First, what is the MAPK pathway?
MAPK stands for mitogen-activated protein kinase. The classification MAPK actually refers to three different kinds of pathways: ERK, JNK, and p38. These pathways contribute to controlling several extremely complex operations within the human body specifically cell growth and death. In a healthy brain, the MAPK pathways are tightly regulated. However, in the previously mentioned diseases, disruption in the MAPK pathways leads to cell death.
In Alzheimer’s disease, oxidative stress within the brain triggers the MAPK pathways JNK and p38. This activation leads to not only cell death but also the formation of senile plaques and neurofibrillary tangles that are characteristics of Alzheimer’s disease.
Similarly, in Parkinson’s disease, oxidative stress within the brain contributes to characteristic pathology. Lewy bodies are to Parkinson’s as senile plaques and neurofibrillary tangles are to Alzheimer’s. These Lewy bodies build up and activate all three MAPK pathways in the brain leading to cell death and inflammation. It is rather unclear as to how this inflammation and cell death leads to the tremors and rigidity seen in Parkinson’s patients as it a disease still being researched.
In Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS), the pathology is caused by the death of motor neurons. This death is thought to be caused by activation of the p38 MAPK pathway. However, in ALS, it is thought that the activation of p38 comes from a mutation in a gene rather than deregulation of the pathways.
As you may have noticed, the relation of MAPK to Alzheimer’s disease, Parkinson’s disease, and ALS are still just hypothesis. However, research into the topic may present helpful resources into finding treatments for these detrimental diseases that affect not only the patient, but also their family and friends. While on the surface, these three diseases seem unrelated, it seems that deep down, they may have the controlled by the same, albeit complicated, pathway.

4 Responses

  1. Lane Simonian

    The key mediator in Alzheimer’s disease (and probably in many other neurodegenerative diseases) is peroxynitrites. Both JNK and p38 are MAP kinases that generate peroxynitrites (ONOO-) and peroxynitrites in turn ensure the continuous activation of these kinases. The first statement is supported by the following research:

    Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.

    The pathways that lead to the activation of MAPK and to peroxynitrite formation can be found in this link(especially the left side of the chart with the activation of phospholipase C).

    Polyphenolic compounds in various fruits, vegetables, spices, and essential oils will inhibit the activation of phospholipase C gamma (although they may spur the activation of phospholipase C beta) and the induction of inducible nitric oxide and the activation of NADPH oxidase thus limiting the formation of peroxynitrites.
    Polyunsaturated fats inhibit the activity of both forms of phospholipase C, thus a diet high in polyphenols and polyunsaturated fats or spices such as in a Mediterranean diet of a diet from India will prevent or delay the onset of Alzheimer’s disease.

    Peroxynitrites are responsible for the following damage in Alzheimer’s disease:

    Oxidation of receptors involved in short-term memory (muscarinic acetlycholine), mood (serotonin and opioid), alertness (dopamine), sleep (melatonin), social recognition (oxytocin), and brain growth (adrenergic).

    The hyperphosphorylation and nitration of tau proteins which results in problems in neurotransmissions.

    A lack of glucose as a result of lipid peroxidation.

    The aggregation of amyloid plaques.

    The nitration of NMDA receptors which results in the influx of calcium and the efflux of glutamate which kill brains cell.

    Every peroxynitrite scavenger ever studied has partially reversed Alzheimer’s disease in vitro, in mice, or in human beings. Methoxyphenols (such as eugenol in rosemary and several other essential oils) and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng have led to significant improvements in cognitive and non-cognitive function in humans (see the clinical trials by Jimbo and colleagues with aromatherapy and Heo with heat-processed ginseng).

    Please share this information with your classmates and professors. It is the key to effectively treating Alzheimer’s disease and possibly several other neurodegenerative diseases.

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