A new hypothesis for Parkinson’s disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics

Abstract

The combination of genetics and genomics in Parkinson´s disease has recently begun to unveil molecular mechanisms possibly underlying disease onset and progression. In particular, catabolic processes such as autophagy have been increasingly gaining relevance as post-mortem evidence and experimental models suggested a participation in neurodegeneration and alpha-synuclein Lewy body pathology. In addition, familial Parkinson´s disease linked to LRRK2 and alpha-synuclein provided stronger correlation between etiology and alterations in autophagy. More detailed cellular pathways are proposed and genetic risk factors that associate with idiopathic Parkinson´s disease provide further clues in dissecting contributions of single players. Nevertheless, the fine-tuning of these processes remains elusive, as the initial stages of the pathways are not yet clarified.In this review, we collect literature evidence pointing to autophagy as the common, downstream target of Parkinsonian dysfunctions and augment current knowledge on the factors that direct the subsequent steps. Cell and molecular biology evidence indicate that p38 signaling underlies neurodegeneration and autoptic observations suggest a participation in neuropathology. Moreover, alpha-synuclein and LRRK2 also appear involved in the p38 pathway with additional roles in the regulation of GTPase signaling. Small GTPases are critical modulators of p38 activation and thus, their functional interaction with aSyn and LRRK2 could explain much of the detailed mechanics of autophagy in Parkinson´s disease.We propose a novel hypothesis for a more comprehensive working model where autophagy is controlled by upstream pathways, such as GTPase-p38, that have been so far underexplored in this context. In addition, etiological factors (LRRK2, alpha-synuclein) and risk loci might also combine in this common mechanism, providing a powerful experimental setting to dissect the cause of both familial and idiopathic disease.

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

“…At the same time, neuropathology has been hypothesized to be a consequence of ALP dysfunction (reviewed in ref. 31 ).…”

Role of Alterations in Protein Kinase p38γ in the Pathogenesis of the Synaptic Pathology in Dementia With Lewy Bodies and α-Synuclein Transgenic Models

“…The main theory is that the progressive age-dependent accumulation and transmission of α-syn multimers result in DNA damage, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, calcium dysregulation, autophagy blockage, and altered kinase signaling that, in turn, produces neurotoxicity and inflammation (Kim et al, 2013Lashuel et al, 2013;Rockenstein et al, 2014;Villar-Pique et al, 2016;Rocha et al, 2018;Kwon et al, 2019;Schaser et al, 2019). Mitogen activated protein kinases (MAPKs), including extracellular signal-related kinases (ERK), c-Jun N terminal kinase (JNK), and p38, have received particular attention among kinase signaling changes because of their roles in cell death signaling, oxidative stress, inflammation, and phosphorylation of α-syn and tau (Bachstetter and Van Eldik, 2010;Jha et al, 2015;Kim and Choi, 2015;He et al, 2018;Obergasteiger et al, 2018). Of these, p38 MAPK, also called stress-activated protein kinase (SAPK), is known to be a key mediator of neuronal plasticity and inflammation in the CNS (Bachstetter and Van Eldik, 2010;Lee and Kim, 2017).…”

Study of the Link Between Neuronal Death, Glial Response, and MAPK Pathway in Old Parkinsonian Mice

“…IL-32b exaggerated the MPTP-mediated activation of p38 MAPK and JNK pathways, which have been shown to be involved in MPTP neurotoxicity (Jung et al, 2017). In fact, a new hypothesis for PD pathogenesis that points out the role of p38 MAPK pathway in the modulation of autophagy in cell death processes has recently been proposed (Obergasteiger et al, 2018). FIGURE 6 | Representative images of TH, Iba-1, and GFAP immunostaining of control and Parkinsonian mice at 48 h after the last 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine hydrochloride (MPTP) injection.…”