Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations

Dehay, Benjamin; Bourdenx, Mathieu; Gorry, Philippe; Przedborski, Serge; Vila, Miquel; Hunot, Stéphane; Singleton, Andrew B.; Olanow, C. Warren; Merchant, Kalpana; Bézard, Erwan; Petsko, Gregory A.; Meissner, Wassilios G.

doi:10.1016/s1474-4422(15)00006-x

Cited by 418 publications

(354 citation statements)

References 123 publications

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“…Although knowledge on various mechanisms underlying Parkinson's disease and other synucleinopathies has been greatly expanded over the last decades, the pathomechanism is still not well-understood [30][31][32]. Different mechanisms have been suggested such as mitochondrial dysfunction, cytoskeletal alterations, enhanced oxidative stress or impairment of protein clearance pathways.…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

“…Different mechanisms have been suggested such as mitochondrial dysfunction, cytoskeletal alterations, enhanced oxidative stress or impairment of protein clearance pathways. SYN plays multiple pivotal roles in these diseases, nowadays its small, soluble oligomeric forms with beta-sheet conformation are considered the most toxic species [30,32,33]. To target SYN toxicity, the current strategies focus on its increased expression level (by gene silencing), aggregation (by anti-aggregation compounds), defective clearance (by autophagy inducers), and/or cell-to-cell propagation of its neurotoxic conformers (by immunotherapy, degrading enzymes) [30,34].…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

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Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Proposed strategies to stop or reduce α-synuclein aggregation include enhancing the levels of heat shock proteins to stabilize protein folding, using compounds with antioxidant or antiaggregant activity, promoting intracellular degradation of α-synuclein, or immunotherapies to clear α-synuclein (reviewed in ref. 4).…”

mentioning

confidence: 99%

Modulating membrane binding of α-synuclein as a therapeutic strategy

Pineda

Burré

2017

Proc. Natl. Acad. Sci. U.S.A.

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α-Synuclein aggregation is a pathological hallmark of Parkinson's disease (PD), Lewy body dementia, multiple system atrophy, and a variety of other synucleinopathies (1). The occurrence of familial PD due to α-synuclein mutations, gene duplication and triplication, as well as polymorphisms in regulatory elements of the α-synuclein gene, supports a causative role of α-synuclein in these neurodegenerative diseases (reviewed in ref.2). In addition, a prion-like spread of α-synuclein pathology has been proposed, by propagation of neurotoxic α-synuclein aggregates from one neuron to the other (3). Attenuating or stopping aggregation of α-synuclein is thus a highly pursued strategy to combat pathology in these diseases (Fig. 1). A number of factors have been reported to influence the aggregation propensity of α-synuclein, including oxidative stress, posttranslational modifications in α-synuclein, and increased local concentration. Proposed strategies to stop or reduce α-synuclein aggregation include enhancing the levels of heat shock proteins to stabilize protein folding, using compounds with antioxidant or antiaggregant activity, promoting intracellular degradation of α-synuclein, or immunotherapies to clear α-synuclein (reviewed in ref. 4).However, none of these approaches has had success in translation to the clinic, and treatments for PD remain symptomatic, focusing on treating the movement disorder symptoms associated with loss of dopaminergic neurons in the substantia nigra pars compacta. Treatment of the nonmotor symptoms is much more challenging and less established, and no therapy is available that slows down or stops the progression of PD. In PNAS, Perni et al. (5) report an inhibitory effect of squalamine-an antimicrobial agent derived from the dogfish shark-on α-synuclein aggregation in vitro and toxicity in vivo, via displacing α-synuclein from phospholipid membranes.Physiologically, α-synuclein exists in a dynamic equilibrium between a natively unfolded cytosolic state and a multimeric membrane-bound state on synaptic vesicles (6, 7). The N-terminal sequence of α-synuclein forms an amphipathic α-helix that mediates association of α-synuclein with lipid membranes (8). This region also contains the non-amyloid-β component (NAC), an area believed to be responsible for α-synuclein aggregation (9). The interaction between α-synuclein and synaptic membranes is believed to be a key feature for mediating its proposed cellular functions: the presynaptic localization of α-synuclein, its interaction with synaptic vesicles and synaptobrevin-2, its SNARE complex-chaperoning activity, its effects on vesicle clustering, and its changes during periods of song acquisition-related synaptic rearrangements in birds (reviewed in ref. 10) strongly suggest that α-synuclein plays a role in neurotransmitter Fig. 1. Physiological and pathological conformations of α-synuclein and strategies to combat α-synuclein aggregation and toxicity. Physiologically, α-synuclein exists in an equilibrium between α-helical multimers bound to syn...

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“…For example, efforts have been taken to block or disrupt α-Syn oligomization in Parkinson's disease with promising outcomes (66). The delineation of the protein-folding crisis and aggregation in hyperglycemia-induced embryonic malformations provides opportunities for developing interventions at multiple levels to prevent birth defects in diabetic pregnancies.…”

Section: Discussionmentioning

confidence: 99%

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Zhao

Cao

Reece

2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8–induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient. Additionally, these aggregates contain the neurodegenerative disease-associated proteins α-Synuclein, Parkin, and Huntingtin (Htt). Aggregation of Htt may lead to formation of a death-inducing signaling complex of Hip1, Hippi, and Caspase-8. Treatment with chemical chaperones, such as sodium 4-phenylbutyrate (PBA), reduces protein aggregation in neural stem cells in vitro and in embryos in vivo. Furthermore, treatment with PBA in vivo decreases NTD rate in the embryos of diabetic mice, as well as Caspase-8 activation and cell death. Enhancing protein folding could be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.

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Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations

Cited by 418 publications

References 123 publications

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Modulating membrane binding of α-synuclein as a therapeutic strategy

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

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