Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Brunden, Kurt R.; Lee, Virginia M.‐Y.; Smith, Amos B.; Trojanowski, John Q.; Ballatore, Carlo

doi:10.1016/j.nbd.2016.12.021

Cited by 85 publications

(100 citation statements)

References 131 publications

(148 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These recent reports support a role for phosphoinositides (PIP)s in mechanisms of PD. Of relevance, α-Syn over expression was shown to associate with impaired cytoskeleton [83,84]; neurite outgrowth and integrity [85]; and membrane trafficking [86]. A common denominator shared by these mechanisms is the involvement of PIPs.…”

Section: Discussionmentioning

confidence: 99%

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

Schechter¹,

Grigoletto

Abd-Elhadi

et al. 2020

Mol Neurodegeneration

View full text Add to dashboard Cite

Background: α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson's disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear.Methods: Biochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains. Results:We analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic α-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for α-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that α-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4, 5-bisphosphate (PI4,5P 2 ). Moreover, our findings link α-Synenhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology. Conclusions:Our results show that through regulating PI4,5P 2 levels, α-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for α-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD.

show abstract

Section: Discussionmentioning

confidence: 99%

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

Schechter¹,

Grigoletto

Abd-Elhadi

et al. 2020

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…In the PS19 tau transgenic mouse model of tauopathy, the brain‐penetrant antimitotic drug epothilone D reduced the burden of tau pathology (Zhang et al, ). Another brain‐penetrant microtubule stabilizer, dictyostatin, also produced improvement in CNS/brain measures (Brunden, Lee, Smith, Trojanowski, & Ballatore, ; Makani et al, ). Note that most antimitotics target microtubule dynamics.…”

Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“…Note that most antimitotics target microtubule dynamics. The possibility remains that their neuroprotective effects occur through microtubule and microtubule‐binding protein‐mediated signaling and/or axonal transport, rather than cell cycle effects (Brunden et al, ; Trojanowski, Smith, Huryn, & Lee, ). There are ongoing translational studies and clinical trials.…”

Section: Effects Of Cell Cycle Interfering Drugs On Ad Modelsmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

View full text Add to dashboard Cite

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

show abstract

“…Correct alignment of the MT and mitotic spindle during cell division is crucial for cell fate determination, tissue organization, and normal development. Mutations associated with spindle disorientation through an increase in MT dynamics lead to an imbalance causing reduced or excessive cell proliferation that can result in cancer, birth disorders and brain diseases [12][13][14][15][16][17]. Altered tubulin isotype expression is the most widely characterized MT alteration reported in cancer [17].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of [11c]mpc-6827 as a Microtubule Targeting Pet Radiotracer in Cancer Cell Lines

Kumar

Prabhakaran²,

Damuka

et al. 2019

Int J Pharm Pharm Sci

View full text Add to dashboard Cite

Objective: The objective of this study was to evaluate the uptake and specificity of [11C]MPC-6827, a MT targeted PET ligand in prostate, glioblastoma and breast cancer cells. Methods: [11C]MPC-6827 was synthesized by reacting corresponding desmethyl precursors with [11C]CH3I in a GE-FX2MeI/FX2M radiochemistry module. In vitro binding of [11C]MPC-6827 was performed in breast cancer MDA-MB-231, glioblastoma (GBM) patient-derived tumor (GBM-PDX), GBM U251 and prostate cancer 3 (PC3) cell lines at 37 °C in quadruplicate at 5, 15, 30, 60, and 90 minute incubation time. The nonspecific bindings were determined by incubation with unlabeled microtubule targeting agents MPC-6827, HD-800, colchicine, paclitaxel and docetaxel (5.0 mM). Results: [11C]MPC-6827 provided the highest binding in the breast cancer cell, MDA-MB-231, among all the cells studied, with 90% specific binding. [11C]MPC-6827 binds to glioblastoma PDX and U251 cells with ~50% and 40% specific binding, whereas, prostate cancer cell line, PC3 cells showed 40% specific binding. [11C]MPC-6827 also exhibits binding to the taxane and colchicine binding sites of MTs, in MDA-MB-231 cells. Conclusion: These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of the brain and peripheral cancers.

show abstract

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Cited by 85 publications

References 131 publications

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson’s disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Evaluation of [11c]mpc-6827 as a Microtubule Targeting Pet Radiotracer in Cancer Cell Lines

Contact Info

Product

Resources

About