Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jun;9(10):1039-1053.
doi: 10.4155/fmc-2017-0016. Epub 2017 Jun 20.

α-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease

Sushil K Singh  1 , Aloke Dutta  2 , Gyan Modi  1
Affiliations
Review

α-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease

Sushil K Singh et al. Future Med Chem. 2017 Jun.

Abstract

Parkinson's disease (PD) is a multifactorial progressive neurological disorder. Pathological hallmarks of PD are characterized by the presence of α-synuclein (αSyn) aggregates known as Lewy bodies. αSyn aggregation is one of the leading causes for the neuronal dysfunction and death in PD. It is also associated with neurotransmitter and calcium release. Current therapies of PD are limited to only symptomatic relief without addressing the underlying pathogenic factors of the disease process such as aggregation of αSyn. Consequently, the progression of the disease continues with the current therapies. Therefore, the modulation of αSyn aggregation is an emerging approach as a novel therapeutic target to treat PD. There are two major aspects that might be targeted therapeutically: first, protein is prone to aggregation, therefore, anti-aggregative or compounds that can break the pre-existing aggregates should be helpful. Second, there are number of molecular events that may be targeted to combat the disease.

Keywords: D-520; Lewy body; Parkinson's disease; molecular tweezers; polyphenols; α-synuclein.

PubMed Disclaimer

Conflict of interest statement

Financial & competing interests disclosure

Part of the work cited in this manuscript is supported by the National Institute of Neurological Disorders and Stroke/National Institute of Health (NS047198, AKD). GP Modi and SK Singh are thankful to Indian Institute of Technology (BHU) for providing seed money (SM/2016-17/1198/L) and Department of Biotechnology (BT/PR9624/MED/30/1253/2013 dated 29/11/2014), respectively, to carry out part of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. Possible therapeutic pathways to modulate α-synuclein aggregation.
<b>Figure 2.</b>
Figure 2.. Mechanism of free radical quenching ability of polyphenols.
<b>Figure 3.</b>
Figure 3.. Comparison of potent and weak α-synuclein aggregation modulators.
<b>Figure 4.</b>
Figure 4.. Polyphenols with ability to modulate αSyn aggregation.
(A) epigallocatechin gallate (EGCG); (B) nordihydroguaiaretic acid (NDGA); (C) apigenin; (D) scutellarein; (E) rifampicin; (F) curcumin; and (G) curcumin-glucoside. αSyn: Alpha-synuclein.
<b>Figure 5.</b>
Figure 5.. Novel small heterocyclic molecules with ability to modulate αSyn aggregation.
(A) selegiline; (B & C) molecular tweezers; (D & E) tryptophan and napthoquinone derivatives; (F) B2; (G & H) SNX-2112 and analog (I & J) D519 and D520; (K & L) 2-pyridone analogs; and (M) ceftriaxone.
See this image and copyright information in PMC

References

    1. Przedborski S. The two-century journey of Parkinson disease research. Nat. Rev. Neurosci. 2017;18(4):251–259. - PubMed
    1. Silva BA, Einarsdottir O, Fink AL, Uversky VN. Biophysical characterization of alpha-synuclein and rotenone interaction. Biomolecules. 2013;3(3):703–732. - PMC - PubMed
    1. Markesbery WR, Jicha GA, Liu H, Schmitt FA. Lewy body pathology in normal elderly subjects. J. Neuropathol. Exp. Neurol. 2009;68(7):816–822. - PMC - PubMed
    1. Emanuele M, Chieregatti E. Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role. Biomolecules. 2015;5(2):865–892. - PMC - PubMed
    1. Yasuda T, Nakata Y, Mochizuki H. α-Synuclein and neuronal cell death. Mol. Neurobiol. 2013;47(2):466–483. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources