Targeting α‐synuclein: Therapeutic options

Abstract

The discovery of the central role of α-synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector-mediated expression of the disease-causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal-autophagic system, through proteasome-mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society.

Proteostasis in cardiac health and disease

“…Next, we highlight seven pos sible pharma cological therapies designed to enhance PQC that are close to clinical testing in cardiac disease (TABLE 2). Therapeutic strategies against proteotoxicity have been reviewed previously 174,175 .…”

Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application

“…Dehay et al aimed to prevent either direct α -synuclein's seeds' toxicity or cell-to-cell transmission and have developed some in vitro screens for compounds targeting these phenomena [94]. Models with human Lewy body-derived α -synuclein assemblies can also be used to prevent cell-to-cell transmission.…”

Challenges in detecting disease modification in Parkinson's disease clinical trials

“…Additionally, there remains the inherent difficulty of assessing the long-term safety of these new treatments, which may target molecular mechanisms involved in other diseases. For example, efforts to target the toxic effects of alpha-synuclein aggregation as a disease modifying strategy using passive and active immunisation with monoclonal antibodies against alpha-synuclein have been found safe in phase 1 trials [29]. However there are theoretical concerns that some species of alpha-synuclein may be protective [30] and the long term consequences of lowering alpha-synuclein may have unforeseen outcomes [29].…”

“…For example, efforts to target the toxic effects of alpha-synuclein aggregation as a disease modifying strategy using passive and active immunisation with monoclonal antibodies against alpha-synuclein have been found safe in phase 1 trials [29]. However there are theoretical concerns that some species of alpha-synuclein may be protective [30] and the long term consequences of lowering alpha-synuclein may have unforeseen outcomes [29]. Alternatively using drugs already in clinical use with well-known safety and pharmacokinetic profiles and "repositioning" them for use in PD may allay some of the short term safety concerns but often long term safety data regarding their use in a novel population (e.g.…”