J Neurochem. 2019 Jul 2. doi: 10.1111/jnc.14806. [Epub ahead of print]

Cellular models of alpha-synuclein toxicity and aggregation.

Delenclos M¹, Burgess JD^1,2, Lamprokostopoulou A³, Outeiro TF^4,5,6, Vekrellis K³, McLean PJ^1,2.

Abstract

Misfolding and aggregation of alpha-synuclein (α-syn) with concomitant cytotoxicity is a hallmark of Lewy body related disorders such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although it plays a pivotal role in pathogenesis and disease progression, the function of α-syn and the molecular mechanisms underlying α-syn-induced neurotoxicity in these diseases are still elusive. Many in vitro and in vivo experimental models mimicking α-syn pathology such as oligomerization, toxicity and more recently neuronal propagation have been generated over the years. In particular, cellular models have been crucial for our comprehension of the pathogenic process of the disease and are beneficial for screening of molecules capable of modulating α-syn toxicity. Here, we review α-syn based cell culture models that reproduce some features of the neuronal populations affected in patients, from basic unicellular organisms to mammalian cell lines and primary neurons, to the cutting edge models of patient-specific cell lines. These reprogrammed cells known as induced pluripotent stem cells (iPSCs) have garnered attention because they closely reproduce the characteristics of neurons found in patients and provide a valuable tool for mechanistic studies. We also discuss how different cell models may constitute powerful tools for high-throughput screening of molecules capable of modulating α-syn toxicity and prevention of its propagation. This article is protected by copyright. All rights reserved.