Back to the tubule: microtubule dynamics in Parkinson's disease.
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.
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.|Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD, 20982-3707, USA.
Laura
L
Pellegrini
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
Andrea
A
Wetzel
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.|Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, Queen Square, London, UK.
Simone
S
Grannó
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
George
G
Heaton
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK. kirsten.harvey@ucl.ac.uk.
Kirsten
0000-0002-1291-0728
K
Harvey
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055808:Drug Discovery; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D014404:Tubulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D014404:Tubulin; D016875:tau Proteins
Axonal transport; Cytoskeleton; LRRK2; Microtubule dynamics; Microtubule targeting agents; PARK genes; Parkinson’s disease; Tau; Wnt signalling