α-Synuclein Aggregation Modulation: An Emerging Approach for the Treatment of Parkinson'S Disease

Singh, Suman Kumar; Dutta, Aloke K.; Modi, Gyan

doi:10.4155/fmc-2017-0016

Cited by 43 publications

(27 citation statements)

References 89 publications

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“…In this fashion, small organic molecules, e.g. polyphenols such as curcumin, have been widely tested for their ability to inhibit α-synuclein aggregation [41,42].…”

Section: Parkinson's Disease Estrogens and Sex Differences Estrogenmentioning

confidence: 99%

Is insulin-like growth factor-1 involved in Parkinson’s disease development?

et al. 2020

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Parkinson's disease (PD) is a neurodegenerative disorder that results in the death of dopaminergic neurons within the substantia nigra pars compacta and the reduction in dopaminergic control over striatal output neurons, leading to a movement disorder most commonly characterized by akinesia or bradykinesia, rigidity and tremor. Also, PD is less frequently depicted by sensory symptoms (pain and tingling), hyposmia, sleep alterations, depression and anxiety, and abnormal executive and working memory related functions. On the other hand, insulin-like growth factor 1 (IGF-1) is an endocrine, paracrine and autocrine hormone with several functions including tissue growth and development, insulin-like activity, proliferation, pro-survival, anti-aging, antioxidant and neuroprotection, among others. Herein this review tries to summarize all experimental and clinical data to understand the pathophysiology and development of PD, as well as its clear association with IGF-1, supported by several lines of evidence: (1) IGF-1 decreases with age, while aging is the major risk for PD establishment and development; (2) numerous basic and translational data have appointed direct protective and homeostasis IGF-1 roles in all brain cells; (3) estrogens seem to confer women strong protection to PD via IGF-1; and (4) clinical correlations in PD cohorts have confirmed elevated IGF-1 levels at the onset of the disease, suggesting an ongoing compensatory or "fight-to-injury" mechanism.

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“…In this fashion, small organic molecules, e.g. polyphenols such as curcumin, have been widely tested for their ability to inhibit α-synuclein aggregation [41,42].…”

Section: Parkinson's Disease Estrogens and Sex Differences Estrogenmentioning

confidence: 99%

Is insulin-like growth factor-1 involved in Parkinson’s disease development?

et al. 2020

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“…Fibrillar formation of αSyn is the predominant form of the accumulated and aggregated αSyn in dopaminergic neurons (28). As shown in Fig.…”

Section: αSyn Fibrils Are Degraded By Ectopic Ncl Expressionmentioning

confidence: 93%

Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

Nam

Jeong

et al. 2020

Preprint

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Background Alpha-synuclein (αSyn) is a major component of Lewy bodies, which are known to be a pathogenic marker of Parkinson’s disease (PD). The accumulation of αSyn is caused by dysfunctions in protein degradation machinery. The reinforcement of αSyn degradation is a potential therapeutic target of PD since accumulated αSyn is responsible for the pathogenesis of PD. Nucleolin (NCL) is essential for forming nucleolar structure. The function of NCL is correlated with oxidative stress-mediated cell death. A previous study demonstrated that NCL was reduced in PD brains, and overexpression of NCL alleviated rotenone-induced neural toxic effects. Knockdown of NCL had the opposite effect. These results suggest that the malfunctioning of NCL would exacerbate PD pathology. Thus, we hypothesized that the introduction of ectopic NCL could rescue the α-synucleinopathy in PD. Methods We tested whether ectopic expression of NCL facilitates the clearance of αSyn. The Ectopic expression of NCL was accomplished by the transfection of GFP or GFP-NCL in mouse embryonic fibroblasts (MEF) or transduction of green fluorescent protein (GFP) or GFP-NCL using lentivirus in rat primary cortical neuron. We also investigated whether the expression of GFP or GFP-NCL in mouse substantia nigra alleviates the PD pathology derived by αSyn aggregates. Results The expression of NCL enhanced the clearance of αSyn accumulation or aggregates in MEF and rat primary cortical neurons. The activity of autophagy-lysosome pathway was enhanced by NCL expression. The transduction of NCL in the substantia nigra, which was co-injected with αSyn fibrils, rescued PD manifestations. Conclusions The elevation of NCL levels may reflect a therapeutic strategy for α-synucleinopathy in PD.

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Section: Future Direction: Amyloid Proteomicsmentioning

confidence: 99%

“…Interestingly, a class of small molecules that act as a chemical chaperone can modulate α‐synuclein aggregation . A large collection of chemically diverse compounds was used for screening . The potential inhibitors of α‐synuclein aggregation are certain polyphenol, flavonoids, curcumin glucoside derivatives, the water soluble “molecular tweezers,” and many other molecules are known to interact with α‐synuclein at its monomeric and/or aggregated states.…”

Section: Future Direction: Amyloid Proteomicsmentioning

confidence: 99%

Formation of Heterotypic Amyloids: α‐Synuclein in Co‐Aggregation

Bhasne

Mukhopadhyay

2018

Proteomics

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Protein misfolding resulting in the formation of ordered amyloid aggregates is associated with a number of devastating human diseases. Intrinsically disordered proteins (IDPs) do not autonomously fold up into a unique stable conformation and remain as an ensemble of rapidly fluctuating conformers. Many IDPs are prone to convert into the β-rich amyloid state. One such amyloidogenic IDP is α-synuclein that is involved in Parkinson's disease. Recent studies have indicated that other neuronal proteins, especially IDPs, can co-aggregate with α-synuclein in many pathological ailments. This article describes several such observations highlighting the role of heterotypic protein-protein interactions in the formation of hetero-amyloids. It is believed that the characterizations of molecular cross talks between amyloidogenic proteins as well as the mechanistic studies of heterotypic protein aggregation will allow us to decipher the role of the interacting proteins in amyloid proteomics.

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α-Synuclein Aggregation Modulation: An Emerging Approach for the Treatment of Parkinson'S Disease

Cited by 43 publications

References 89 publications

Is insulin-like growth factor-1 involved in Parkinson’s disease development?

Is insulin-like growth factor-1 involved in Parkinson’s disease development?

Expression of transduced Nucleolin promotes the clearance of accumulated alpha-synuclein

Formation of Heterotypic Amyloids: α‐Synuclein in Co‐Aggregation

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