The more I read about neurochemical systems and associated diseases and disorders, the more I get a sense for how vast the problems and intricacies for treatment are and how much work there is to be done. Signaling systems are intertwined with other processes, proteins have multiple functions, and often there are multiple contributing factors to a disease, making targeting for disease treatment extremely difficult. As with any problem, there are many possible routes to solve these health problems, and one of the first steps is determining which routes are most effective and feasible.
Fairly recently, studies have determined the mitogen-activated protein kinase (MAPK) system as an integral contributor to neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), and Amyotrophic lateral sclerosis (ALS). The general layout of the MAPK has several steps: typically, stimuli activates a MAP4 kinase enzyme, the MAP4 kinase phosphorylates a MAP3 kinase, which in turn phosphorylates a MAP2 kinase, which in turn phosphorylates a MAP kinase, resulting in phosphorylation of various proteins including transcription factors, all ending in a cellular response. In short, there is a phosphorylation cascade with at least three enzyme intermediates before a protein is affected that induces a cellular response. The three most common MAPK pathways are called ERK, p38, and JNK.
Alzheimer’s disease is characterized by β-amyloid plaques in the brain and neurofibrillary tangles leading to neuronal apoptosis (cell death). The MAPK system plays a role in AD in a few different ways. Oxidative stress provides conditions for JNK and p38 to be activated, which then directly or indirectly activate the β- and γ-secretases, leading to β-amyloid plaques and neuronal apoptosis. Also, kinases such as JNK, p38, and ERK mediate the phosphorylation of the protein tau, which results in neurofibrillary tangles and apoptosis. Lastly, the JNK and p38 pathways have been shown to directly induce neuronal apoptosis, contributing to AD pathogenesis.
The main characteristic of Parkinson’s disease is a loss of dopaminergic neurons. As opposed to that in AD, the role of MAPK in PD is seemingly a secondary factor for its pathogenesis. The primary factors in the development of PD involve a defective gene encoding a defective protein which then activates MAPK signaling. One mechanism starts with a defective α-synuclein protein which aggregates, activating MAPK signaling, resulting in inflammation and dopamine neuron death. Another mechanism involves the p38 pathway inducing the expression of the protein Bax which, along with α-synuclein aggregates, decreases mitochondrial viability and leads to dopaminergic apoptosis. Still another mechanism involves the JNK and p38 pathways; the defective, mutant proteins parkin and DJ-1 can activate the JNK and p38 pathways leading to dopaminergic apoptosis.
Amyotrophic lateral sclerosis is characterized by a selective loss of motor neurons. The primary cause for this is thought to be a mutation in the SOD1 gene and protein, causing activation of the JNK and p38 signaling pathways. Overactivation of p38 has been shown to correlate with motor neuron degeneration, directly relating the p38 pathway with ALS development.
In describing the roles of MAPK pathways in these neurodegenerative disorders, I glossed over a fair number of intermediate steps. Many intermediate steps do exist with these mechanisms, however, which generally means that altering one component may result in many unwanted side effects down the cascade; a bigger system means it’s more complex and a bigger pain in the neck, unfortunately. This makes me skeptical as to whether the MAPK system would really be effective as a target for treatment; it is involved in so many different processes and often can lead to both positive and negative cell responses, including cell growth as well as death. Instead of MAPK inhibitors, I would suggest gene therapy for some of the mutations involved in these diseases, or perhaps an increase in mitochondrial protection. Forgive me for the football reference, but if a team is doing poorly, they either have to beef up the offense to attack the opponent more effectively or strengthen their defense to deter the opponent’s advances. In this case, I’m wary of going on the offensive to destroy the MAPK system, so better protection may be a safer and more effective route since a lack of protection from oxidative stress is a widespread factor in neuronal cell death. As always, more time and research will tell!
MAPK: the Wrong Way?
