Pathological and clinical aspects of alpha/beta synuclein in Parkinson’s disease and related disorders

ABSTRACT

Parkinson’s disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using β-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.

KEYWORDS:

• α-synuclein
• β-synuclein
• immunotherapy
• Parkinson’s disease
• multiple system atrophy
• disease-modifying therapy

Acknowledgment

This work is dedicated in memory of Prof. Eldad Melamed who was a mentor, scientist, and explorer.

Declaration of interest

The authors were supported by Dexcel Pharma Ltd. M Tolmasov and Y Gilgun-Sherki are employees of Dexcel Pharma Ltd. R Djaldetti reports paid lectures from Teva, Abbvie and Novartis. N Lev received consulting fees from UGH Pharma. 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.