LAUSR

Of several identified loci, Syt-11, the encoding gene for synaptotagmin-11, is of the hottest PD risk genes. Syt-11 is a non-Ca-binding Syt and cause the inhibition of neural endocytosis and therefor vesicle recycling. Of note, a robust body of in vitro studies exhibited that parkin, an E3 ubiquitin ligase whose mutations are critical in etiopathology of familial recessive and sporadic early-onset PD, leads to Syt-11 ubiquitination and that Syt-11 aggregations were detected in the brain of PD patients. Herein, Wang and colleagues demonstrated that Syt-11 is a parkin substrate and a mediator of PD-like neurotoxicity and behavioral disturbances. First, it was shown that knockdown of parkin expression leads to the accumulation of Syt-11 in SNpc of mice, providing strong evidence that Syt-11 levels are directly determined by parkin via ubiquitin-dependent proteasome degradation. The results from methamphetamine-induced rotational asymmetry showed that unilateral overexpression of Syt-11 led to escalated ipsilateral rotation and also progressively diminished time latency to rotation. Moreover, 1 month after injection, mice with unilateral Syt-11 overexpression had deranged gait and contralateral stride length, implying that Syt-11 possesses the ability to cause locomotor behavioral deficits. Afterward, Wang and colleagues tried to determine whether Syt-11 had detrimental effects on dopamine release and dopaminergic neural survival. Syt-11 was sufficient to suppress dopamine release as they demonstrated that dopamine discharge was decreased in ipsilateral striatum of mice with unilateral Syt-11 overexpression compared to the contralateral striatum of the same mice and the ipsilateral striatum of the control group. Despite behavioral locomotor and dopamine discharge deficits, the overexpression of Syt11 did not cause dopaminergic loss 1 month after vector injection, but approximately 35% dopaminergic loss was found 3 months after injection, demonstrating that aggregation of Syt-11 gives rise to late-onset dopaminergic neuron death. Wang and colleagues had previously documented that Syt-11 inhibits dynamin-dependent endocytosis 29. Using Syt-11-overexpressing transgenic mice, they corroborated that Syt-11 accumulation decelerated clathrin-mediated endocytosis. They proved that the overexpression of Syt-11, in particular, its cannabinoid 2 (CB2) domain, leads to the suppression of vesicle recycling. Altogether, it was substantiated that Syt-11 is a key inhibitor of dopaminergic transmission primarily through the alternation of endocytosis and vesicle recycling. Wang and colleagues manipulated lentiviral vectors for the knockdown of Syt-11 and parkin to determine whether Syt-11 is critical for the mediation of parkin-associated neurotoxicity. The results indicated the parkin-dependent impaired dopamine transmission requires Syt-11 aggregation. Collectively, this impressive work provides the first in vivo evidence demonstrating the role of Syt-11 in the mediation of parkin-associated PD-like manifestations. Thus, targeting Syt-11 accumulation may be used in PD clinical settings. Nonetheless, further studies are required to see whether reduced dopamine release can completely justify the pathologic effects of Syt-11 accumulation.