Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Feb;74(3):409-434.
doi: 10.1007/s00018-016-2351-6. Epub 2016 Sep 6.

Back to the tubule: microtubule dynamics in Parkinson's disease

Laura Pellegrini  1   2 , Andrea Wetzel  1 , Simone Grannó  1   3 , George Heaton  1 , Kirsten Harvey  4
Affiliations
Review

Back to the tubule: microtubule dynamics in Parkinson's disease

Laura Pellegrini et al. Cell Mol Life Sci. 2017 Feb.

Abstract

Cytoskeletal homeostasis is essential for the development, survival and maintenance of an efficient nervous system. Microtubules are highly dynamic polymers important for neuronal growth, morphology, migration and polarity. In cooperation with several classes of binding proteins, microtubules regulate long-distance intracellular cargo trafficking along axons and dendrites. The importance of a delicate interplay between cytoskeletal components is reflected in several human neurodegenerative disorders linked to abnormal microtubule dynamics, including Parkinson's disease (PD). Mounting evidence now suggests PD pathogenesis might be underlined by early cytoskeletal dysfunction. Advances in genetics have identified PD-associated mutations and variants in genes encoding various proteins affecting microtubule function including the microtubule-associated protein tau. In this review, we highlight the role of microtubules, their major posttranslational modifications and microtubule associated proteins in neuronal function. We then present key evidence on the contribution of microtubule dysfunction to PD. Finally, we discuss how regulation of microtubule dynamics with microtubule-_targeting agents and deacetylase inhibitors represents a promising strategy for innovative therapeutic development.

Keywords: Axonal transport; Cytoskeleton; LRRK2; Microtubule dynamics; Microtubule _targeting agents; PARK genes; Parkinson’s disease; Tau; Wnt signalling.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Microtubule structure and dynamic instability. Microtubules are long, dynamic, cylindrical polymers with a diameter of 15–25 nm. Each microtubule is composed by 13 protofilaments of α/β-tubulin heterodimers, which assemble forming a tubular structure (a). At microtubule plus ends, GTP-bound β-tubulin caps growing filaments, attracting further GTP-bound α/β-tubulin heterodimers. Upon binding of a new heterodimer, β-tubulin GTP on the filament undergoes hydrolysis at the ‘exchangeable’ site (E-site), ensuring the GTP cap remains on the first heterodimer (b) [27, 36]. The cyclic incorporation and loss of GTP β-tubulin, stochastically alternates growing (rescue) stable and depolymerising states (catastrophe). The ‘non-exchangeable’ site (N-site) is occupied by the intradimeric, α-tubulin-bound GTP, and ensures structural stability [35, 36]. Crystal structure of tubulin from PDB [http://www.rcsb.org/pdb/pv/pv.do?pdbid=1TUB&bionumber=1], mechanism adapted from [36]
Fig. 2
Fig. 2
Cytoskeletal distribution in growth cones. At the growth cone, F-actin extends the plasma membrane forming filopodia and polymerises in bundles. These F-actin bundles associate with dynamic and growing microtubules to promote axon outgrowth. Stable microtubule bundles are present in the centre of growth cones
Fig. 3
Fig. 3
Post-translational modifications of tubulin. Overview of post-translational modifications (PTMs) of tubulin including _target sites, associated enzymes and known effects. Microtubules in subcellular compartments are functionally and structurally distinguished, with stable and dynamic axonal microtubules presenting differential PTM distributions
Fig. 4
Fig. 4
Microtubule-mediated axonal transport. Axonal microtubules are specialised in transmitting vesicles and other cargo via molecular motors. Microtubule organisation and modulation by MAPs (such as tau) also aids transport. Kinesin (left red) performs anterograde transport to axonal terminals. Dynein (right yellow) moves retrogradely towards the cell body. Fast and slow axonal transports drive organelles, vesicles and proteins along the axon. A tight balance of anterograde, bidirectional and retrograde transport is required to avoid either accumulation or depletion of cellular components [40]
Fig. 5
Fig. 5
Effect of PD-linked proteins on microtubules. Overview of microtubule effects mediated by mutations in known PD-related genes, including inheritance patterns. All of the discussed proteins have demonstrated varying degrees of tubulin binding and the ability to modify microtubule function via several distinct mechanisms. Parkin structure adapted from [160]
Fig. 6
Fig. 6
Microtubule-_targeting agents (MTAs). Overview of microtubule _targeting agents as potential therapeutic strategies. A variety of compounds has been shown to exert beneficial effects on microtubule PTMs, stability and transport. Additionally, the outlined agents are all reportedly able to produce improvements in PD-associated, model phenotypes. MTAs are also characterised by low toxicity at microtubule-modifying doses [Reference for chemical structures: https://www.ncbi.nlm.nih.gov/pccompound]
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386:896–912. doi: 10.1016/S0140-6736(14)61393-3. - DOI - PubMed
    1. Albin RL, Young AB, Penney JB. The functional-anatomy of basal ganglia disorders. Trends Neurosci. 1989;12:366–375. doi: 10.1016/0166-2236(89)90074-X. - DOI - PubMed
    1. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–535. doi: 10.1016/S1474-4422(06)70471-9. - DOI - PubMed
    1. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res Rev. 2014;14:19–30. doi: 10.1016/j.arr.2014.01.004. - DOI - PMC - PubMed
    1. Mehanna R, Moore S, Hou JG, Sarwar AI, Lai EC. Comparing clinical features of young onset, middle onset and late onset Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:530–534. doi: 10.1016/j.parkreldis.2014.02.013. - DOI - PubMed

MeSH terms

LinkOut - more resources

  NODES
twitter 2