Microtubule-associated Protein 1B Is a Component of Cortical Lewy Bodies and Binds α-Synuclein Filaments

Jensen, Poul Henning; Islam, Khalid; Kenney, John M.; Nielsen, Morten S.; Power, John H.; Gai, Wei

doi:10.1074/jbc.m000099200

Cited by 135 publications

(109 citation statements)

References 34 publications

(49 reference statements)

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“…These proteins fell into a number of discrete functional groupings. Thirty-nine of these were cytoskeletal proteins, including microtubule-associated protein 1B (MAP1B) previously reported to interact with the carboxyl terminus of ␣-synuclein (26). Our new finding is the significant enrichment for interaction with MAP1B when ␣-synuclein was phosphorylated.…”

Section: Quantitative Analysis Of Proteins Pulled Down With Differentsupporting

confidence: 49%

“…The interaction of MAP1B with the carboxyl-terminal 45 amino acids of ␣-synuclein has been observed previously, although an increased affinity with phosphorylation was not previously recognized (26). A striking and novel observation in the pulldown using phosphorylated peptide was the prominence of non-erythrocyte ␣II and ␤II spectrins (fodrins) and the spectrin-interacting proteins ankyrin and band 4.1B (27,28).…”

Section: Proteins With No Detectable Phosphorylation-dependent Affinitymentioning

confidence: 79%

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Proteomics Analysis Identifies Phosphorylation-dependent α-Synuclein Protein Interactions

McFarland

Ellis

Markey

et al. 2008

Molecular & Cellular Proteomics

162

143

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Mutations and copy number variation in theHere we used the combination of peptide pulldown assays and mass spectrometry to identify and compare protein-protein interactions of phosphorylated and nonphosphorylated ␣-synuclein. We showed that non-phosphorylated ␣-synuclein carboxyl terminus pulled down protein complexes that were highly enriched for mitochondrial electron transport proteins, whereas ␣-synuclein carboxyl terminus phosphorylated on either Ser-129 or Tyr-125 did not. Instead the set of proteins pulled down by phosphorylated ␣-synuclein was highly enriched in certain cytoskeletal proteins, in vesicular trafficking proteins, and in a small number of enzymes involved in protein serine phosphorylation. This targeted comparative proteomics approach for unbiased identification of protein-protein interactions sug-

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Section: Quantitative Analysis Of Proteins Pulled Down With Differentsupporting

confidence: 49%

Section: Proteins With No Detectable Phosphorylation-dependent Affinitymentioning

confidence: 79%

Proteomics Analysis Identifies Phosphorylation-dependent α-Synuclein Protein Interactions

McFarland

Ellis

Markey

et al. 2008

Molecular & Cellular Proteomics

162

143

View full text Add to dashboard Cite

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“…In addition, we found that mimicking αS phosphorylation increased the number of inclusions per cell. NMR spectroscopy suggests that the enhanced aggregation is due to a direct binding of Rab8a to the C-terminus of αS that has been implicated in interactions with a variety of protein partners (Burre et al, 2010;De Genst et al, 2010;Jensen et al, 1999Jensen et al, , 2000Kawamata et al, 2001;Kim et al, 2002;Yap et al, 2011). Thus, our study provides a link between physiological αS interactions and pathogenic aggregation.…”

Section: Discussionmentioning

confidence: 79%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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“…Both GAPDH and HSP70 were centrifuged for 30 min at 120,000 rpm at 4°C in a TLA 120.1 rotor in a Optima TLX centrifuge (Beckman Instruments) to remove any aggregated materials prior to pull-down experiments. Recombinant human full-length AS-(1-140), C-terminally truncated AS-(1-95), and ␤-synuclein were expressed in Escherichia coli and purified as described previously (27,28), followed by an additional reverse phase-high pressure liquid chromatography purification step on a Jupiter C18 column (Phenomenex) in 0.1% trifluoroacetic acid with an acetonitrile gradient. The proteins were subsequently aliquoted, lyophilized, and stored at Ϫ80°C.…”

Section: Methodsmentioning

confidence: 99%

Proteasomal Inhibition by α-Synuclein Filaments and Oligomers

Lindersson

Beedholm

Højrup

et al. 2004

Journal of Biological Chemistry

366

310

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A unifying feature of many neurodegenerative disorders is the accumulation of polyubiquitinated protein inclusions in dystrophic neurons, e.g. containing ␣-synuclein, which is suggestive of an insufficient proteasomal activity. We demonstrate that ␣-synuclein and 20 S proteasome components co-localize in Lewy bodies and show that subunits from 20 S proteasome particles, in contrast to subunits of the 19 S regulatory complex, bind efficiently to aggregated filamentous but not monomeric ␣-synuclein. Proteasome binding to insoluble ␣-synuclein filaments and soluble ␣-synuclein oligomers results in marked inhibition of its chymotrypsin-like hydrolytic activity through a non-competitive mechanism that is mimicked by model amyloid-A␤ peptide aggregates. Endogenous ligands of aggregated ␣-synuclein like heat shock protein 70 and glyceraldehyde-6-phosphate dehydrogenase bind filaments and inhibit their anti-proteasomal activity. The inhibitory effect of amyloid aggregates may thus be amenable to modulation by endogenous chaperones and possibly accessible for therapeutic intervention.

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Microtubule-associated Protein 1B Is a Component of Cortical Lewy Bodies and Binds α-Synuclein Filaments

Cited by 135 publications

References 34 publications

Proteomics Analysis Identifies Phosphorylation-dependent α-Synuclein Protein Interactions

Proteomics Analysis Identifies Phosphorylation-dependent α-Synuclein Protein Interactions

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Proteasomal Inhibition by α-Synuclein Filaments and Oligomers

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