Parkinson's disease and translational research

Abstract

Parkinson's disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

Keywords: Aggresome; Autophagy; Dopamine deficiency; Medium spiny neurons; Pre-formed fibrils; Protein aggregates; α-Synuclein.

Fig. 1

Aggregation, transport and clearance of α-synuclein. a Concept of aggregation and spreading: After ribosomal translation of pathogenic α-synuclein (aSyn), monomers (1) form oligomers (2) and primary nucleation with formation of the first aggregate takes place. Subsequent steps are fibril elongation (3) and secondary nucleation with formation of further nuclei, e.g. by fibrils breaking (4). The aggregates are transported along the axonal projections, secreted and taken up by a neighboring cell (5). The aggregation of aSyn monomers is greatly enhanced by addition of even small quantities of aggregates, which serve as nuclei and replace the slow step of primary nucleation by the faster step of secondary nucleation. This process is called seeding (6). b Transport and autophagic clearance of aSyn: Aggregates are dynein-dependently transported to the perinuclear region to form aggresomes. Parts of the cytosol containing aggregates get engulfed by a membrane to form autophagosomes. Subsequently, Rab7 regulates the trafficking of autophagosomal and lysosomal vesicles and their fusion towards autolysosomes, followed by degradation of the vesicle content. There is also evidence for the secretion via exosomal release

Fig. 2

α-Synuclein particles and acidic compartments by light microscopy. a Deconvolved confocal images of live HEK293T cells transfected with A53T-α-synuclein (Syn)-EGFP and treated with lysotracker red for 2 h at 37 °C. Arrows show an aggresome. Note the distribution of lysotracker-positive vesicles close to the aggresome and other αSyn aggregates. b Deconvolved confocal image of HEK293T cells transfected with A53T-α-Syn-mCherry, the lysosomal marker LAMP1-EGFP and the cargo protein p62 without fluorescent tag. Enlarged insets show a cluster of LAMP1-decorated vesicles colocalizing with aSyn. Arrow shows a large aggresome, so called “p62 body”. c Deconvolved confocal image of HEK293T cells transfected with A53T-α-syn-EGFP and a biosensor of the autophagosome lipid phosphatidylinositol 3-phosphate (PI3P) tagged to mCherry. Enlarged insets show the PI3P-positive vesicles around the aggresome (arrow), consistent with the hypothesis that autophagosomes degrade aggresomes. In panels b-c, the red and green channels of the insets are shown individually next to the merged images. Scale bars, 5 μm. Original data

Fig. 3

α-Synuclein and autophagy. a HEK293 cells were transfected with EGFP-tagged A53T-α-synuclein and manually classified due to the distribution of EGFP. a1 A representative example of homogenous distribution of EGFP, as the healthy phenotype. a2 A representative example of a cell containing an aggresome. Scale bars, 5 μm. b HEK293 cells were transfected with EGFP-tagged A53T-α-synuclein and the dominant negative version of autophagy-related protein 5 (Atg5). Significances from t-test; n = 3 independent experiments. c HEK293 cells were transfected with EGFP-tagged A53T-α-synuclein and cells were incubated with 0.2 μM Bafilomycin A1 (BafA1) for 4 h to block autophagy or with 5 μM proteasome inhibitor MG132 for 4 h. Starvation was induced by complete medium exchange for Hank’s balanced salts (HBSS) for 4 h. One-way ANOVA was significant, results from post-hoc test are indicated (n = 3 independent experiments). Graphs represent mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. Original data

Fig. 4

Schematic representation of the basal ganglia circuitry and changes observed in PD patients and models. Distinct loops exist for motor, limbic and associative circuitry. The basal ganglia disinhibit desired motor patterns and inhibit competing motor patterns. The circuitry includes the direct pathway from striatum to GPi/SNr, gated by D1 dopamine receptors, the indirect pathway through GPe and STN, gated by D2 dopamine receptors, and the hyperdirect pathway from cortex to STN. The striatal circuitry is modulated in addition by M4 muscarine and A2A adenosine receptors. In PD, changes occur not only in the firing rate (in particular increased rate of STN firing), but also in the firing patterns, notably the pathological beta-oscillation and increased firing in bursts. Chronic dopamine deficiency leads to the (homeostatic) changes in MSN excitability and morphology. Display of circuitry inspired by Hutchison et al., 2004 [91]. Blue arrows indicate GABAergic projections, and red arrows indicate glutamatergic projections. Abbreviations: p, pathway; rec., receptor; STN, subthalamic nucleus; GPe, globus pallidus pars externa; GPi, globus pallidus pars interna; SNr, substantia nigra pars reticulata; MSN, medium spiny neurons