title: Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.
abstract: The disordered tubulin polymerization promoting protein (TPPP/p25) was found to be co-enriched in neuronal and glial inclusions with α-synuclein in Parkinson disease and multiple system atrophy, respectively; however, co-occurrence of α-synuclein with β-amyloid (Aβ) in human brain inclusions has been recently reported, suggesting the existence of mixed type pathologies that could result in obstacles in the correct diagnosis and treatment. Here we identified TPPP/p25 as an interacting partner of the soluble Aβ oligomers as major risk factors for Alzheimer disease using ProtoArray human protein microarray. The interactions of oligomeric Aβ with proteins involved in the etiology of neurological disorders were characterized by ELISA, surface plasmon resonance, pelleting experiments, and tubulin polymerization assay. We showed that the Aβ(42) tightly bound to TPPP/p25 (K(d) = 85 nm) and caused aberrant protein aggregation by inhibiting the physiologically relevant TPPP/p25-derived microtubule assembly. The pair-wise interactions of Aβ(42), α-synuclein, and tubulin were found to be relatively weak; however, these three components formed soluble ternary complex exclusively in the absence of TPPP/p25. The aggregation-facilitating activity of TPPP/p25 and its interaction with Aβ was monitored by electron microscopy with purified proteins by pelleting experiments with cell-free extracts as well as by confocal microscopy with CHO cells expressing TPPP/p25 or amyloid. The finding that the interaction of TPPP/p25 with Aβ can produce pathological-like aggregates is tightly coupled with unusual pathology of the Alzheimer disease revealed previously; that is, partial co-localization of Aβ and TPPP/p25 in the case of diffuse Lewy body disease with Alzheimer disease.
authors.affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1113 Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Oláh
authors.forename: Orsolya
authors.initials: O
authors.lastname: Vincze
authors.forename: Dezsõ
authors.initials: D
authors.lastname: Virók
authors.forename: Dóra
authors.initials: D
authors.lastname: Simon
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bozsó
authors.forename: Natália
authors.initials: N
authors.lastname: Tõkési
authors.forename: István
authors.initials: I
authors.lastname: Horváth
authors.forename: Emma
authors.initials: E
authors.lastname: Hlavanda
authors.forename: János
authors.initials: J
authors.lastname: Kovács
authors.forename: Anna
authors.initials: A
authors.lastname: Magyar
authors.forename: Mária
authors.initials: M
authors.lastname: Szũcs
authors.forename: Ferenc
authors.initials: F
authors.lastname: Orosz
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D040081:Protein Array Analysis; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; C118136:TPPP protein, human; C539090:TPPP protein, rat; D014404:Tubulin; D051844:alpha-Synuclein