**2. Conclusions**

Consistent with the critical role of MAPKs in key cellular activities including cell proliferation, differentiation, and survival or death. The MAPK signaling pathways have been implicated in the pathogenesis of many human diseases. Various observations suggest that they contribute to Parkinson's disease-related pathological processes such as oxidative stress, neuro-inflammation, autophagy, and neuronal death (Figure 2). In addition, MAPK inhibitors demonstrate important neuroprotective properties upstream of the execution of apoptosis in dopaminergic neurons. Therefore, discovering the relationship between MAPK pathways and the prominent pathological processes observed during Parkinson's disease progression may not only aid us to understand the etiology of this disease but also lend insight into molecular targets for the development of therapeutic drugs.

**Figure 2.** Involvement of MAPKs in processes that lead to Parkinson's disease pathology. Different stimuli (stress stimuli, growth factors, cytokines, mitogens, pathogens, toxins) induce activation of MAPK pathways including activation of MAPKKK and MAPKK followed by phosphorylation of downstream targets such as JNKs, p38 MAPKs, and ERK1/2. JNKs and p38 MAPKs are grouped together due to their involvement in the "death pathway" (marked in red) while ERK1/2 is believed to promote cell growth and differentiation (marked in green). Activation of JNKs and p38 MAPKs promote oxidative stress and apoptosis, which are main contributors to PD pathogenesis. Oxidative stress may also cause microglial activation and chronic inflammation, which are toxic for brain cells and leads to PD pathology. In addition, ERK1/2 contribute to apoptosis of brain cells through the activation of NFAT and p53 and to neuronal inflammation through the activation of STATs. Both ERK1/2 and JNKs activate mTOR signaling, which promotes neurodegeneration such as that observed in PD.

**Author Contributions:** Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the article content. (1) Authors who made substantial contributions to the concept and design of the review: A.B., A.F., and G.N. (2) Authors who participated in drafting the article: A.B., G.N., and A.F. (3) All Authors gave the final approval of the version to be submitted.

**Acknowledgments:** Authors would like to thank W. Le´sniak for a critical reading of the manuscript. This work has been supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no 665735 (Bio4Med) and by the funding from the Polish Ministry of Science and Higher Education within 2016–2020 funds for the implementation of international projects (agreement no 3548/H2020/COFUND/2016/2) by NCN grant 2014/15/B/NZ4/05041 to GN and by statutory funds from the Nencki Institute of Experimental Biology PAS.

**Conflicts of Interest:** The authors declare no conflict of interest.
