Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications

Guo, Wenting; Dittlau, Katarina Stoklund; Bosch, Ludo Van Den

doi:10.1016/j.semcdb.2019.07.010

Cited by 138 publications

(134 citation statements)

References 181 publications

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“…Mitochondrial dynamics and mitochondrial axonal transport play a crucial role in neuronal growth and survival (Lovas and Wang, 2013;Mandal and Drerup, 2019). Several studies have suggested that altered mitochondrial dynamics and improper axonal transport are the early events of the onset of many neurodegenerative diseases (Guo et al, 2020;Kay et al, 2018). Miro is the sole protein that plays a vital role in the bi-directional mitochondrial axonal transport such as anterograde transport (from cell body to axon) and retrograde transport (from axon to cell body) via forming a major protein complex with Milton (adaptor protein), kinesin and dynein (motor proteins) (Russo et al, 2009;Cai and Sheng, 2009;Panchal and Tiwari, 2018).…”

Section: Discussionmentioning

confidence: 99%

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42andAppl) inDrosophila melanogaster

Panchal

Tiwari

2020

Biology Open

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Miro (mitochondrial Rho GTPases), a mitochondrial outer membrane protein, facilitates mitochondrial axonal transport along the microtubules to facilitate neuronal function. It plays an important role in regulating mitochondrial dynamics (fusion and fission) and cellular energy generation. Thus, Miro might be associated with the key pathologies of several neurodegenerative diseases (NDs) including Alzheimer's disease (AD). In the present manuscript, we have demonstrated the possible genetic interaction between Miro and AD-related genes such as Tau, Aβ42 and Appl in Drosophila melanogaster. Ectopic expression of Tau, Aβ42 and Appl induced a rough eye phenotype, defects in phototaxis and climbing activity, and shortened lifespan in the flies. In our study, we have observed that overexpression of Miro improves the rough eye phenotype, behavioral activities (climbing and phototaxis) and ATP level in AD model flies. Further, the improvement examined in AD-related phenotypes was correlated with decreased oxidative stress, cell death and neurodegeneration in Miro overexpressing AD model flies. Thus, the obtained results suggested that Miro genetically interacts with AD-related genes in Drosophila and has the potential to be used as a therapeutic target for the design of therapeutic strategies for NDs.This article has an associated First Person interview with the first author of the paper.

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Section: Discussionmentioning

confidence: 99%

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42andAppl) inDrosophila melanogaster

Panchal

Tiwari

2020

Biology Open

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“…The details of tau-microtubule interactions, the dynamism of adsorption-desorption (detachment) processes, has been analyzed very recently [160]. Big tau aggregates may be involved in axonal transport defects, causing a direct physical blockade of the transport [187].…”

Section: Pathophysiological Effects Of Tau Assembliesmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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“…Notably, all these pathways are associated to the hallmarks of aging (Kennedy et al, 2014;Sun et al, 2016;Deepa et al, 2018;Haas, 2019;Lautrup et al, 2019;Royce et al, 2019;McReynolds et al, 2020). In the context of AD, different pathogenic pathways have been shown to contribute to axon demise, including calcium signaling imbalance, mitochondrial dysfunction, alterations in axonal transport, and increased oxidative stress (Bamburg and Bloom, 2009;Yu et al, 2009;Ye et al, 2012;Cioffi et al, 2019;Guo et al, 2020). As stated above, the accumulation of misfolded proteins constitutes a salient feature of AD neuropathology and a large body of evidence linking Aβ and tau pathologies with the disruption of axons has been published.…”

Section: Introductionmentioning

confidence: 99%

Axonal Degeneration in AD: The Contribution of Aβ and Tau

Salvadores

Gerónimo‐Olvera

Court

2020

Front. Aging Neurosci.

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Alzheimer's disease (AD) represents the most common age-related neurodegenerative disorder, affecting around 35 million people worldwide. Despite enormous efforts dedicated to AD research over decades, there is still no cure for the disease. Misfolding and accumulation of Aβ and tau proteins in the brain constitute a defining signature of AD neuropathology, and mounting evidence has documented a link between aggregation of these proteins and neuronal dysfunction. In this context, progressive axonal degeneration has been associated with early stages of AD and linked to Aβ and tau accumulation. As the axonal degeneration mechanism has been starting to be unveiled, it constitutes a promising target for neuroprotection in AD. A comprehensive understanding of the mechanism of axonal destruction in neurodegenerative conditions is therefore critical for the development of new therapies aimed to prevent axonal loss before irreversible neuronal death occurs in AD. Here, we review current evidence of the involvement of Aβ and tau pathologies in the activation of signaling cascades that can promote axonal demise.

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Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications

Cited by 138 publications

References 181 publications

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42andAppl) inDrosophila melanogaster

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42andAppl) inDrosophila melanogaster

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Axonal Degeneration in AD: The Contribution of Aβ and Tau

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