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

NEUROBIOLOGY OF DISEASE

卷:145

Article

Siddu, Alberto^1,2  David, Linda Suzanne^1,2  Lauinger, Nadine³  Chen, Xiuqing^3,4  Saint-Pierre, Martine²  Alpaugh, Melanie^1,2  Durcan, Thomas^3,4  Cicchetti, Francesca^1,2 

[1] CHU Quebec, Axe Neurosci, Ctr Rech, 2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada

[2] Univ Laval, Dept Psychiat & Neurosci, 1050 Ave Med, Quebec City, PQ G1V 0A6, Canada

[3] McGill Univ, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada

[4] Montreal Neurol Hosp & Inst, 3801 Univ St, Montreal, PQ H3A 2B4, Canada

关键词: Thy1-alpha-Syn mice;    Cystamine;    Neurodegenerative diseases;    alpha-Syn;    alpha-Syn phosphorylation;    alpha-Syn fibrillation;    6-OHDA;    Neurorestoration;    Parkinson's disease;   

DOI  :  10.1016/j.nbd.2020.105042

来源: Elsevier

【 摘 要 】

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 alpha-Synuclein (alpha-Syn), one of the main hallmarks of PD. We therefore tested the efficacy of cysteamine on the Thy1-alpha-Syn mouse model which over-expresses full-length human wild-type alpha-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 alpha-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 alpha-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 alpha-Syn.