How Cell-Permeable Peptides Targeting JNK Pathways Could Prevent Neuron Loss

One of the biggest problems when developing a treatment for neurodegenerative diseases is the problematic search to identify molecules, peptides, or any other component able to cross the blood-brain barrier or the cell membrane. In recent years, the discovery of the so-called cell-penetrating peptides (CPPs) has changed the course of research programs since using CPPs helps in carrying non-permeable molecules like peptides, drugs, proteins, and others to not only cross the blood-brain barrier but also the cell membrane (see Fig. 1).[7] Several investigations demonstrated that there are CPPs like TAT with neuroprotective properties.[9] TAT is one of the best and shortest CPPs with a great carrying capacity, transporting several drugs and other molecules to the brain without problem. Different studies tested TAT neuroprotection in vivo and in vitro, showing promising results in both types of experiments.[9] Thanks to these neuroprotective characteristics, TAT and other CPPs has been combined with other peptides for treating neurodegenerative disorders like Alzheimer’s (AD) and Parkinson’s disease (PD) (see Fig 1).[7] One of the most studied ways to prevent neuronal loss is inhibiting the JNK family, which has a crucial role in apoptosis.[1,4-6] The JNK (c-Jun-N-terminal protein kinase) family mainly comprises the JNK-1, JNK-2, and JNK-3 kinases.[9] Kinases have a vital role in the cells by controlling the increase or decrease of molecular processes like development, plasticity, autophagy, and other essential activities for the well-functioning of an organism. While JNK-1 and JNK-2 are found almost everywhere in the body, JNK- 3 is found principally in the testes and the brain.[9] Several investigations show that inhibiting these kinases gives neuroprotection and avoids the progression of some disorders like AD and PD due to direct participation in the disease’s pathology. [4-7] Initially, the researchers started to test the inhibition of JNK-3 since it is primarily found in the brain, obtaining good results in neuroprotection.[2] Also, other investigations tested the combination of TAT with a peptide called JNKI-1D developed to inhibit JNK apoptosis pathway participation activated by the pathology of AD or PD.[9] The resulting peptide called JNKI-1D-TAT possesses neuroprotective properties, thus preventing neuronal loss in PD and AD models. However, different studies show that inhibiting JNK-1 and JNK-2 or all members of the JNK family increases the neuroprotection ability. ^[8,9,11] All these investigations demonstrated the need to inhibit not only the JNK-3 but most or all the components of the JNK family. [5-7]

Neuroprotective features of CPPs in combination with other molecules or peptides for treating PD and AD.

Figure 1.

JNK family participates in the apoptosis pathway, also known as programmed cell death.[4] The apoptosis mechanism is used to eliminate cells that are damaged in anyway. This mechanism is suitable for healthy people because it helps avoid developing cancer and other disorders.[1] On the other hand, apoptosis is detrimental in neurodegenerative diseases that share the abnormal accumulation of misfolded proteins, contributing to dementia, cognitive loss, memory loss, behavioral problems, and sleep problems, among others, through neuronal cell loss.[3,5,7] In addition, the JNK family also participates in pathways related to regulation, plasticity, development of the Central Nervous System (CNS), inflammation, and autophagy.[9] The well-functioning of all these processes is vital. Recent studies suggested that an imbalance of the JNK family members can accelerate the progression of both AD and PD pathologies. One of the hallmarks of AD is the aggregation of amyloid beta (Aβ) in the extracellular area.[7] The overexpression of Aβ triggers the activation of JNK-3, which also participates in the formation of Aβ42, a toxic species that affects the neuron’s cell function when it accumulates.[7] It is unclear whether the neurodegenerative disorder or the JNK imbalance comes first. However, they both have a direct relationship where PD and AD patients show high levels of JNK in the brain (postmortem), and irregular levels of the JNK family accelerate the progression of both disorders (see Fig. 2). [5,9] JNK imbalance could also lead to increased inflammation responses, low plasticity, and a flaw in autophagy performance, among other related adverse effects. An increase in apoptosis in PD and AD patients causes a decrease in neurons in the brain, affecting cognitive, behavioral, and memory performance.[8] JNK also decreases the α-syn accumulation in PD models, contributing to neuroprotection.[10] JNK pathway influence positively many vital processes of the body unless an imbalance occurs. [2,8] JNK has been the target for treating several diseases like cancer, strokes, PD, AD, Huntington’s disease, and other neurodegenerative disorders, showing promising results. More investigations need to be done to comprehend better how the correct levels of JNK can help combat important hallmarks of degenerative illnesses to eventually prevent or revert the progression of related diseases like PD and AD. In general, the benefits of inhibiting JNKs for treating neurodegenerative disorders are:

­Improving autophagy for the elimination of misfolded proteins (Aβ (AD), tau protein (AD), and α-syn (PD)

• ­Increasing cell proliferation.
• Decreasing programmed cell death.
• Reducing brain damage.
• Decreasing cognitive decline.
• Increasing gene expression.
• Decreasing neuroinflammation responses
• Improving memory
• Providing neuroprotection
• Improving synaptic connections

High levels of JNKs is associated with AD, PD, and other disorders.

Figure 2.

References

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