Investigational α-synuclein aggregation inhibitors: hope for Parkinson’s disease

ABSTRACT

Introduction: The therapeutic management of Parkinson’s disease (PD) is challenging and has not been fully resolved. The main challenges include motor fluctuations and levodopa-induced dyskinesia. Moreover, no disease-modifying or neuroprotective therapy is currently available.

Areas covered: This review focuses on α-synuclein aggregation inhibitors and their therapeutic role in PD, with special attention to heat shock proteins, immunotherapy (active and passive), the potential of targeting the Ser129 phosphorylation site, and the antibiotic possibilities.

Expert opinion: The induction of chaperones may provide beneficial strategy to target synucleinopathies, but further investigations are needed to find the best options. The promising preclinical results with immunotherapy suggest that it may be a valuable disease-modifying therapy in PD in the future. Clinical trials are currently in the initial phases, and future studies need to confirm the beneficial therapeutic effect in humans and clarify open questions as regards the exact mode of action and potential safety concerns. In case of covalent modifications, phosphorylation of α-synuclein is of outstanding importance; however, conflicting results and open questions exist which necessitate clarification. In vitro results suggest that several antibiotics may also influence α-synuclein aggregation, but these results are to be confirmed in the future.

KEYWORDS:

• α-synuclein aggregation inhibitor
• heat shock proteins
• immunotherapy
• Parkinson’s disease
• phase I
• phase II
• preclinical

Article highlights

• Manipulations related to heat shock proteins are promising approaches in preventing α-synuclein oligomerization and toxicity.

• Being successful at the preclinical level, immunotherapeutic approaches against α-synuclein oligomers have already entered the clinical phases of investigation.

• Results as regards Ser129 phosphorylation are controversial and necessitate clarification.

• Some well-known antibiotics showed promise as molecules interfering with α-synuclein aggregation, and are to be tested in clinical trials.

• Several natural polyphenols are implicated as potent inhibitors of α-synuclein aggregate formation, warranting further investigations at both preclinical and clinical levels.

• Peptide inhibitors are novel promising molecules in the field with currently limited data available, which necessitates further examinations at the preclinical level.

This box summarizes key points contained in the article.

Acknowledgments

We are thankful for the linguistic corrections to Dr Levente Szalárdy.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the project TÁMOP-4.2.6.3.1., the Hungarian Brain Research Program (NAP, Grant No. KTIA_13_NAP-A-III/9., KTIA_13_NAP-A-II/17., and KTIA_13_NAP-A-II/18.), and the MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences and the University of Szeged.