Abstract:The pathological interaction of intrinsically disordered proteins, such as α-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25), is often associated with neurodegenerative disorders. These hallmark proteins are co-enriched and co-localized in brain inclusions of Parkinson's disease and other synucleinopathies; yet, their successful targeting does not provide adequate effect due to their multiple functions. Here we characterized the interactions of the human recombinant wild type SYN, its t… Show more
“…The distinct interface of the physiological and pathological complexes is a crucial point in our drug targeting strategy. Our analysis revealed that the 147 KAPIISGVTK 156 segment in the flexible CORE region of TPPP/p25 and the 126 EMPSEEGYQDYEPEA 140 segment of the C-terminus of SYN are involved in the formation of the interface of their pathological complex [36]. Massive intracellular aggregation of the N-and C-terminally-truncated TPPP/p25 and SYN or its fragments was established.…”
Section: U N C O R R E C T E D P R O O Fmentioning
confidence: 82%
“…Recently we have suggested a new strategy for the therapeutic treatment of Parkinson's disease by targeting the interface of the pathological TPPP/p25-SYN complex without influencing the physiological interaction of TPPP/p25 with tubulin/microtubules [35,36]. The distinct interface of the physiological and pathological complexes is a crucial point in our drug targeting strategy.…”
Section: U N C O R R E C T E D P R O O Fmentioning
confidence: 99%
“…Both the co-enrichment and the co-localization of TPPP/p25 and SYN were detected in brain inclusions of patients suffering from Parkinson's disease and multiple system atrophy [16]; the direct associations of the two disordered proteins were characterized at molecular and cellular levels [35,36]. In addition, the CORE region (45-174 aa) of TPPP/p25, specifically the 147-156 aa segment of this protein, was suggested by ELISA experiments to be localized at the interface in the TPPP/p25-SYN pathological complex [35].…”
Section: Nmr Spectroscopy Of the Syn Binding To The Core Region Of Tpmentioning
The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.
“…The distinct interface of the physiological and pathological complexes is a crucial point in our drug targeting strategy. Our analysis revealed that the 147 KAPIISGVTK 156 segment in the flexible CORE region of TPPP/p25 and the 126 EMPSEEGYQDYEPEA 140 segment of the C-terminus of SYN are involved in the formation of the interface of their pathological complex [36]. Massive intracellular aggregation of the N-and C-terminally-truncated TPPP/p25 and SYN or its fragments was established.…”
Section: U N C O R R E C T E D P R O O Fmentioning
confidence: 82%
“…Recently we have suggested a new strategy for the therapeutic treatment of Parkinson's disease by targeting the interface of the pathological TPPP/p25-SYN complex without influencing the physiological interaction of TPPP/p25 with tubulin/microtubules [35,36]. The distinct interface of the physiological and pathological complexes is a crucial point in our drug targeting strategy.…”
Section: U N C O R R E C T E D P R O O Fmentioning
confidence: 99%
“…Both the co-enrichment and the co-localization of TPPP/p25 and SYN were detected in brain inclusions of patients suffering from Parkinson's disease and multiple system atrophy [16]; the direct associations of the two disordered proteins were characterized at molecular and cellular levels [35,36]. In addition, the CORE region (45-174 aa) of TPPP/p25, specifically the 147-156 aa segment of this protein, was suggested by ELISA experiments to be localized at the interface in the TPPP/p25-SYN pathological complex [35].…”
Section: Nmr Spectroscopy Of the Syn Binding To The Core Region Of Tpmentioning
The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.
“…Co‐enrichment and co‐localization of TPPP /p25 and SYN in CHO cells taken up from the medium and in human brain tissues of MSA , PD and AD (mixed type pathology) . Figure reproduced from . Written permission has been obtained from Elsevier.…”
Section: Tppp/p25: the New Hallmark Of Parkinsonismmentioning
confidence: 99%
“…The interaction of TPPP/p25 with SYN has been extensively characterized in our laboratory by a wide repertoire of methodologies including biochemical, biophysical and bioinformatics methods using wild‐type and mutant human recombinant proteins, as well as living cell models for immunofluorescence microscopic studies coupled with or without bimolecular fluorescence complementation technology .…”
Section: Targeting Syn and Tppp/p25: A New Strategy To Address The Chmentioning
With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio‐economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α‐synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co‐enriched and co‐localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN‐TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.
Anomalies in neuronal cell architecture, in particular dendritic complexity and synaptic density changes, are widely observed in the brains of subjects with schizophrenia or mood disorders. The concept that a disturbed microtubule cytoskeleton underlies these abnormalities and disrupts synaptic connectivity is supported by evidence from clinical studies and animal models. Prominent changes in tubulin expression levels are commonly found in disease specific regions such as the hippocampus and prefrontal cortex of psychiatric patients. Genetic linkage studies associate tubulinbinding proteins such as the dihydropyrimidinase family with an increased risk to develop schizophrenia and bipolar disorder. For many years, altered immunoreactivity of microtubule associated protein-2 has been a hallmark found in the brains of individuals with schizophrenia. In this review, we present a growing body of evidence that connects a dysfunctional microtubule cytoskeleton with neuropsychiatric illnesses. Findings from animal models are discussed together with clinical data with a particular focus on tubulin posttranslational modifications and on microtubule-binding proteins. V C 2016 Wiley Periodicals, Inc.Key Words: microtubule; depression; schizophrenia; MAP2; JNK Introduction I t is almost 50 years since tubulin was identified as the globular protein that makes up microtubules [Mohri, 1968]. Tubulin polymers, or microtubules, along with actin microfilaments and intermediate filaments, make up the cytoskeletal framework, which provides structure and dynamics to cells [Wells, 2005]. Neuronal cells are exceptional in their usage of microtubules to generate a highly polarized morphology consisting of long axons and dendritic arbors that form the receptive field for electrochemical input. Axonal microtubules are polarized and confer the rigidity that is necessary for long distance transport, whereas dendritic microtubules show mixed polarity and influence processes such as arborization and signaling to dendritic spines .In cells, a and b tubulin exist as heterodimers. They are structurally homologous, comprising two b-strands surrounded by a-helices. Each subunit is divided into three functional domains: the N-terminal domain that incorporates a nucleotide-binding region (i.e., GTP), an intermediate domain comprising the taxol-binding site, and a Cterminal domain which provides the binding surface for motor proteins [Nogales et al., 1998]. a/b heterodimers interact in a head-to-tail conformation giving rise to linear polymers with inherent polarity known as protofilaments [Black and Baas, 1989]. Typically, a microtubule consists of a cylindrical assembly of 13 protofilaments with a diameter of 25 nm, and highly variable length. Microtubules actively modify their structure through dynamic cycles of assembly and disassembly. The plus end where b-tubulin is exposed elongates more rapidly than the a-tubulin exposed, minus end [Horio et al., 2014]. The process of rapid growth and collapse of microtubules is known as dynamic instability a...
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