Beneficial effects of cysteamine in Thy1-α-Syn mice and induced pluripotent stem cells with a SNCA gene triplication

• Main Authors: Alberto Siddu, Linda Suzanne David, Nadine Lauinger, Xiuqing Chen, Martine Saint-Pierre, Melanie Alpaugh, Thomas Durcan, Francesca Cicchetti
• Format: Article
• Language: English
• Published: Elsevier 2020-11-01
• Series: Neurobiology of Disease
• Subjects: Thy1-α-Syn mice; Cystamine; Neurodegenerative diseases; α-Syn; α-Syn phosphorylation; α-Syn fibrillation
• Online Access: http://www.sciencedirect.com/science/article/pii/S096999612030317X

A number of publications have reported that cysteamine has significant therapeutic effects on several aspects of Parkinson's disease (PD)-related pathology but none of these studies have evaluated its impact on pathological forms of α-Synuclein (α-Syn), one of the main hallmarks of PD. We therefore tested the efficacy of cysteamine on the Thy1-α-Syn mouse model which over-expresses full-length human wild-type α-Syn. Two-month (early stage disease) and 6-month old (late stage disease) mice and littermate controls were treated daily with cysteamine (20 mg/kg, i.p.) to assess the protective and restorative properties of this compound. After 6 weeks of treatment, animals were tested using a battery of motor tests. Cysteamine-treated transgenic mice displayed significant improvements in motor performance as compared to saline-treated transgenic littermates. Post-mortem readouts revealed a reduction in fibrillation, phosphorylation and total levels of overexpresed human α-Syn. To determine if such outcomes extended to human cells, the benefits of cysteamine were additionally tested using 6-hydroxydopamine (6-OHDA) treated neurons differentiated from induced pluripotent stem cells (iPSCs) derived from a PD patient harbouring a triplication of the SNCA gene. SNCA neurons treated with cysteamine exhibited significantly more intact/healthy neurites than cells treated with 6-OHDA alone. Additionally, SNCA neurons treated with cysteamine in the absence of 6-OHDA showed a trend towards lower total α-Syn levels. Overall, our in vivo and in vitro findings suggest that cysteamine can act as a disease-modifying molecule by enhancing -the survival of dopaminergic neurons and reducing pathological forms of α-Syn.