Impaired intracellular trafficking defines early Parkinson's disease

Abstract

Parkinson's disease (PD) is an insidious and incurable neurodegenerative disease, and represents a significant cost to individuals, carers, and ageing societies. It is defined at post-mortem by the loss of dopamine neurons in the substantia nigra together with the presence of Lewy bodies and Lewy neurites. We examine here the role of α-synuclein and other cellular transport proteins implicated in PD and how their aberrant activity may be compounded by the unique anatomy of the dopaminergic neuron. This review uses multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells, and refined animal models to argue that prodromal PD can be defined as a disease of impaired intracellular trafficking. Dysfunction of the dopaminergic synapse heralds trafficking impairment.

Keywords: Parkinson's disease; Tau; cell trafficking; α-synuclein.

Figure 1

Complex axonal arborisation of midbrain dopaminergic neurons. (A) Medial, dorsal, and frontal reconstructions of the axonal projections of midbrain dopaminergic neurons generated using a GFP protein targeting neuronal membranes. Red (striosome) and blue (matrix) lines indicate the striatal compartments in which axonal fibres are located. (B) Striatal arborisation of a typical midbrain dopaminergic neuron projected onto the parasagittal plane. Figures adapted from Matsuda et al. with permission from the Society for Neuroscience. Abbreviations: ac, anterior commissure; cc, corpus callosum; cp, cerebral peduncle; CPu, caudate-putamen (neostriatum); GPe, external segment of the globus pallidus; GPi, globus pallidus interna; Hpc, hippocampus; ic, internal capsule; LV, lateral ventricle; ml, medial lemniscus; ot, optic tract; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STh, subthalamic nucleus; str, superior thalamic radiation; Th, thalamus; ZI, zona incerta.

Figure 2

Synaptic dystrophy in Parkinson's disease. (A) Tight regulation of synaptic dopamine (DA) release is achieved by SNARE-mediated vesicle docking, together with chaperone molecules cysteine string protein-α (CSPα) and the synucleins. Autophagosomes are able to leave the synapse, hence preventing protein accumulation. (B) α-Synuclein disrupts synaptic physiology. The presence of oligomeric α-synuclein impairs SNARE function, decreasing intervesicular space, reducing the number of synaptic vesicles, and impairing DA release. Autophagosomes fuse with lysosomes in the cell body, but are prevented from leaving the synapse, and MAPT haplotype differences may contribute to impaired axonal transport of autophagosomes.

Figure 3

Intracellular trafficking is impaired in Parkinson's disease (PD). (A) The pathological and physiological species of α-synuclein remain unknown; however, increasing evidence suggests that oligomers are responsible for the majority of the early deleterious effects. (B) Recent findings demonstrate that α-synuclein impairs key events in the soma, such as ER–Golgi trafficking, endosomal trafficking, and autophagolysosome formation. (C) The most significant genetic risk factor for sporadic PD is the gene for the microtubule-associated protein tau (MAPT). The key function of the tau protein is to regulate microtubule stability, allowing efficient axonal transport, thus providing a mechanism by which MAPT variants confer PD susceptibility. Increased α-synuclein also impairs axonal transport. (D) At the synapse, α-synuclein disturbs DA trafficking and synaptic vesicle distribution. Importantly, synaptic autophagosomes must be trafficked to the soma for protein degradation.

Figure 4

Relationship of tau with axonal transport. (A) Differential expression of tau protein isoforms arise from translation of MAPT splice variants. The MAPT H1 haplotype is directly oriented, whereas the H2 haplotype is due to an inverted sequence of approximately 970 kb. Alternative splicing events at exons 2 and 3 generate tau protein with zero (0N), one (1N), or two (2N) N-terminal repeats. Tau protein with three (3R) or four (4R) tandem repeats is generated from alternative splicing at exon 10. H1 causes relatively increased expression of exon 10, and therefore 4R tau. H2 causes increased exon 3 expression, and therefore 2N tau. Figure adapted from Wade-Martins . (B) Comparison of axonal transport in healthy and Parkinson's disease (PD) dopaminergic neurons. In healthy brain, an increasing tau gradient from proximal to distal helps to drive axonal transport mediated by transport proteins, particularly kinesin and dynein. In the PD brain, risk-associated MAPT variants increase 4R tau expression, which is more prone to aggregation. α-Synuclein impairs axonal transport. Autophagosomes must be cleared from the synapse to the soma to fuse with the lysosome for protein degradation, but this clearance is reduced as a result of axonal trafficking impairment.

Figure I

The α-synuclein protein, in schematic form (A) and its micelle-bound structure (B) solved using nuclear magnetic and electron paramagnetic resonance (taken from the Protein Databank, ID: 1XQ8 [115]). It is divided into three domains, the amphipathic region, the non-amyloid-β component of Alzheimer's disease amyloid (NAC) domain, and the C-terminal acidic tail.