Fig. 1

Molecular interactions between LRRK2, aSyn and p38 MAPK in the regulation of apoptosis and autophagy. Apoptosis and autophagy are the main cellular processes modulated by p38 MAPK. Upstream regulation appears similar, with membrane receptor stimulation coupling to Rho/Ras signaling, activation of MKKs and of p38. In the apoptotic pathway, p38 mainly targets p53 that, when phosphorylated, translocates to the nucleus and promotes gene transcription of the apoptosis mediators Bax and Puma. On the other hand, p38 could also modulate ALP with consequences on protein aggregate degradation (aSyn, Tau). LRRK2 and aSyn probably intervene in this pathway redirecting to one side or the other, depending on the stimuli. LRRK2 can phosphorylate MKKs and/or p38 directly, while aSyn might affect p38 activation through different mechanisms. The initial stages of the cascade, i.e. the specific GTPase (sub)family, could participate as director of the cellular pathway to be activated down the line