Parkinson’s disease: what the model systems have taught us so far

Abstract

Parkinson's disease (PD) is a debilitating neurodegenerative disorder, for which people above the age of 60 show an increased risk. Although there has been great advancement in understanding the disease-related abnormalities in brain circuitry and development of symptomatic treatments, a cure for PD remains elusive. The discovery of PD associated gene mutations and environmental toxins have yielded animal models of the disease. These models could recapitulate several key aspects of PD, and provide more insights into the disease pathogenesis. They have also revealed novel aspects of the disease mechanism including noncell autonomous events and spreading of pathogenic protein species across the brain. Nevertheless, none of these models so far can comprehensively represent all aspects of the human disease. While the field is still searching for the perfect model system, recent developments in stem cell biology have provided a new dimension to modelling PD, especially doing it in a patient-specific manner. In the current review, we attempt to summarize the key findings in the areas discussed above, and highlight how the core PD pathology distinguishes itself from other neurodegenerative disorders while also resembling them in many aspects.

Modeling Parkinson’s Disease: Not Only Rodents?

“…However, in this case, the analysis of the state of the central nervous system can only be assessed by indirect signs, such as the level of metabolites in the cerebrospinal fluid, peripheral, blood and other biological fluids.One of the possible solutions to the problem is the analysis of disease models, in which it is possible to conduct a detailed in-depth study of all aspects of the pathological process, starting from its earliest stages. A lot of modeling options are offered (Dauer and Przedborski, 2003;Danek et al, 2017;Ghatak et al, 2018;Kin et al, 2019;Chia et al, 2020). An analysis of studies published in the 2,000 s suggests that toxic models in rodents are used in the vast majority of cases (Kin et al, 2019).…”

Microglial histamine H4R in the pathophysiology of Parkinson’s disease—a new actor on the stage?

“…Third, it is unclear, whether the rotenone-induced rat model of PD fully reflects all pathophysiological aspects of human PD. Rotenone, which is also used as an insecticide, causes dopaminergic cell death by inhibiting the mitochondrial complex I (Ghatak et al 2018). The same mechanism of action is used in PD models obtained by administration of MPTP (1methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or the herbicide paraquat (N, N′-dimethyl-4,4′-bipyridinium dichloride) (Ghatak et al 2018).…”

“…Rotenone, which is also used as an insecticide, causes dopaminergic cell death by inhibiting the mitochondrial complex I (Ghatak et al 2018). The same mechanism of action is used in PD models obtained by administration of MPTP (1methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or the herbicide paraquat (N, N′-dimethyl-4,4′-bipyridinium dichloride) (Ghatak et al 2018). Alternatively, destruction of dopaminergic neurons and PD-like symptoms can be achieved by administration of 6-hydroxydopamine.…”

“…Alternatively, destruction of dopaminergic neurons and PD-like symptoms can be achieved by administration of 6-hydroxydopamine. Gene-based models make use of mutations in genes associated with human PD, e.g., α-synuclein, leucine-rich repeat kinase, or parkin (Ghatak et al 2018). Thus, future studies should investigate the effect of H 4 R ligands on various animal models of PD, addressing different aspects of this devastating disease.…”

Efeitos do exercício físico na função e biogênese mitocondrial em modelo de doença de Parkinson induzido por 6-hidroxidopamina.

“…Os modelos com toxina são capazes de induzir a morte dos neurônios dopaminérgicos observada na patologia, e têm sido muito utilizados. Dentre essas toxinas estão o 1-metil-1,2,3,6-tetra-hidropiridina (MPTP), o paraquat, a rotenona e a 6-hidroxidopamina (6-OHDA) (SIMOLA; MORELLI;CARTA, 2007;GHATAK et al, 2018).…”