Microtubule-Associated Proteins with Regulatory Functions by Day and Pathological Potency at Night

The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeleton, including the microtubule network. Microtubules play crucial roles achieved by their decoration with proteins/enzymes as well as by posttranslational modifications. This review focuses on the Tubulin Polymerization Promoting Protein (TPPP/p25), a new microtubule associated protein, on its “regulatory functions by day and pathological functions at night”. Physiologically, the moonlighting TPPP/p25 modulates the dynamics and stability of the microtubule network by bundling microtubules and enhancing the tubulin acetylation due to the inhibition of tubulin deacetylases. The optimal endogenous TPPP/p25 level is crucial for its physiological functions, to the differentiation of oligodendrocytes, which are the major constituents of the myelin sheath. Pathologically, TPPP/p25 forms toxic oligomers/aggregates with α-synuclein in neurons and oligodendrocytes in Parkinson’s disease and Multiple System Atrophy, respectively; and their complex is a potential therapeutic drug target. TPPP/p25-derived microtubule hyperacetylation counteracts uncontrolled cell division. All these issues reveal the anti-mitotic and α-synuclein aggregation-promoting potency of TPPP/p25, consistent with the finding that Parkinson’s disease patients have reduced risk for certain cancers.

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Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure

Molecular Biology of the Cell ◽

10.1091/mbc.e13-07-0387 ◽

2014 ◽

Vol 25 (2) ◽

pp. 257-266 ◽

Cited By ~ 98

Author(s):

Stuart C. Howes ◽

Gregory M. Alushin ◽

Toshinobu Shida ◽

Maxence V. Nachury ◽

Eva Nogales

Keyword(s):

Posttranslational Modifications ◽

Luminal Surface ◽

Microtubule Associated Proteins ◽

Interaction Sites ◽

Tubulin Acetylation ◽

Cryo Electron Microscopy ◽

Site Of Action ◽

Associated Proteins ◽

Tubulin Structure ◽

Microtubule Structure

Tubulin undergoes posttranslational modifications proposed to specify microtubule subpopulations for particular functions. Most of these modifications occur on the C-termini of tubulin and may directly affect the binding of microtubule-associated proteins (MAPs) or motors. Acetylation of Lys-40 on α-tubulin is unique in that it is located on the luminal surface of microtubules, away from the interaction sites of most MAPs and motors. We investigate whether acetylation alters the architecture of microtubules or the conformation of tubulin, using cryo–electron microscopy (cryo-EM). No significant changes are observed based on protofilament distributions or microtubule helical lattice parameters. Furthermore, no clear differences in tubulin structure are detected between cryo-EM reconstructions of maximally deacetylated or acetylated microtubules. Our results indicate that the effect of acetylation must be highly localized and affect interaction with proteins that bind directly to the lumen of the microtubule. We also investigate the interaction of the tubulin acetyltransferase, αTAT1, with microtubules and find that αTAT1 is able to interact with the outside of the microtubule, at least partly through the tubulin C-termini. Binding to the outside surface of the microtubule could facilitate access of αTAT1 to its luminal site of action if microtubules undergo lateral opening between protofilaments.

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P3-387 Polychlorinated biphenyls alter expression of Parkinson's disease associated proteins in human neuroblastoma cells and in the rat brain

Neurobiology of Aging ◽

10.1016/s0197-4580(04)81536-7 ◽

2004 ◽

Vol 25 ◽

pp. S465-S466

Author(s):

Katarzyna Malkiewicz ◽

Roma Mohammed ◽

Ronnie Folkesson ◽

Bengt Winblad ◽

Miroslaw Szutowski ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Polychlorinated Biphenyls ◽

Rat Brain ◽

Neuroblastoma Cells ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Associated Proteins

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The role of posttranslational modifications of α-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2018.11.017 ◽

2019 ◽

Vol 1865 (8) ◽

pp. 1992-2000 ◽

Cited By ~ 9

Author(s):

Edward Pajarillo ◽

Asha Rizor ◽

Jayden Lee ◽

Michael Aschner ◽

Eunsook Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Environmental Factors ◽

Posttranslational Modifications

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Intracellular Proadrenomedullin-Derived Peptides Decorate the Microtubules and Contribute to Cytoskeleton Function

Endocrinology ◽

10.1210/en.2007-1763 ◽

2008 ◽

Vol 149 (6) ◽

pp. 2888-2898 ◽

Cited By ~ 20

Author(s):

Dan L. Sackett ◽

Laurent Ozbun ◽

Enrique Zudaire ◽

Lisa Wessner ◽

John M. Chirgwin ◽

...

Keyword(s):

Posttranslational Modifications ◽

Morphological Changes ◽

Microtubule Associated Proteins ◽

Microtubule Stabilization ◽

Gene Coding ◽

Intracellular Compartments ◽

Associated Proteins ◽

G2 Phase ◽

Interfering Rna

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are secretory hormones, but it is not unusual to find them in intracellular compartments. Using yeast-2 hybrid technology, we found interactions between AM and several microtubule-associated proteins (MAPs), and between PAMP and tubulin. Expression of fluorescent-tagged AM and PAMP as well as immunofluorescence for the native peptides showed a complete decoration of the microtubules and colocalization with other MAPs. PAMP, but not AM, bound to tubulin in vitro and destabilized tubulin polymerization. Down-regulation of the gene coding for both AM and PAMP through small interfering RNA technology resulted in morphological changes, microtubule stabilization, increase in posttranslational modifications of tubulin such as acetylation and detyrosination, reduction in cell motility, and partial arrest at the G2 phase of the cell cycle, when compared with cells transfected with the same vector carrying a scrambled sequence. These results show that PAMP is a novel MAP, whereas AM may be exerting more subtle effects in regulating cytoskeleton function.

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Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1922741117 ◽

2020 ◽

Vol 117 (33) ◽

pp. 20305-20315 ◽

Cited By ~ 3

Author(s):

Kun Zhao ◽

Yeh-Jun Lim ◽

Zhenying Liu ◽

Houfang Long ◽

Yunpeng Sun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Posttranslational Modifications ◽

Cortical Neurons ◽

Amyloid Fibrils ◽

Lewy Bodies ◽

Interaction Network ◽

Lewy Neurites ◽

Cryo Electron Microscopy ◽

Fibril Structure

Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

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Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

Cells ◽

10.3390/cells9112485 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2485

Author(s):

Charysse Vandendriessche ◽

Arnout Bruggeman ◽

Caroline Van Cauwenberghe ◽

Roosmarijn E. Vandenbroucke

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Progression ◽

Extracellular Vesicles ◽

Neurodegenerative Disorders ◽

Neuronal Damage ◽

Protein Aggregates ◽

Pathological Changes ◽

Associated Proteins ◽

The Brain

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

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Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

Parkinson s Disease ◽

10.4061/2011/693761 ◽

2011 ◽

Vol 2011 ◽

pp. 1-20 ◽

Cited By ~ 16

Author(s):

A. R. Esteves ◽

D. M. Arduíno ◽

D. F. F. Silva ◽

C. R. Oliveira ◽

S. M. Cardoso

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neuronal Cell ◽

Alpha Synuclein ◽

Vital Role ◽

Microtubule Network ◽

The Road ◽

Species Production ◽

Alpha Synuclein Aggregation

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

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