SYNJ1 rescues motor functions in hereditary and sporadic Parkinson's disease mice by upregulating TSP-1 expression

• Published in: Behavioural brain research Vol. 452; p. 114569
• Main Authors: Tian, Yueqin, Yi, Shang, Guo, Wanyun, Feng, Cuilian, Zhang, Xiufen, Dong, Huateng, Wang, Kaitao, Li, Runtong, Tian, Yuanxin, Gan, Min, Wu, Ting, Xie, Haiting, Gao, Xiaoya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 24.08.2023
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Motor disorders; Neuroblastoma - drug therapy; Neuroprotection; Neuroprotective Agents - pharmacology; Parkinson Disease - drug therapy; Parkinson Disease - genetics; Parkinson’s disease; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; SYNJ1; Thrombospondin 1; TSP-1; TSP-1; SYNJ1; Parkinson’s disease; Motor disorders
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2023.114569

This study aimed to explore the role of SYNJ1 in Parkinson's disease (PD) and its potential as a neuroprotective factor. We found that SYNJ1 was decreased in the SN and striatum of hSNCA*A53T-Tg and MPTP-induced mice compared to normal mice, associated with motor dysfunction, increased α-synuclein and decreased tyrosine hydroxylase. To investigate its neuroprotective effects, SYNJ1 expression was upregulated in the striatum of mice through injection of the rAdV-Synj1 virus into the striatum, which resulted in the rescue of behavioral deficiencies and amelioration of pathological changes. Subsequently, transcriptomic sequencing, bioinformatics analysis and qPCR were conducted in SH-SY5Y cells following SYNJ1 gene knockdown to identify its downstream pathways, which revealed decreased expression of TSP-1 involving extracellular matrix pathways. The virtual protein-protein docking further suggested a potential interaction between the SYNJ1 and TSP-1 proteins. This was followed by the identification of a SYNJ1-dependent TSP-1 expression model in two PD models. The coimmunoprecipitation experiment verified that the interaction between SYNJ1 and TSP-1 was attenuated in 11-month-old hSNCA*A53T-Tg mice compared to normal controls. Our findings suggest that overexpression of SYNJ1 may protect hSNCA*A53T-Tg and MPTP-induced mice by upregulating TSP-1 expression, which is involved in the extracellular matrix pathways. This suggests that SYNJ1 could be a potential therapeutic target for PD, though more research is needed to understand its mechanism.