活性依赖的突触抑制和突触稳态的分子机制

常规RNA干涉或基因敲除的功能缺失手段仅仅只是简单地移除某个基因或蛋白，而这个过程常常会掩盖磷酸化对某个特定蛋白的调节。在树突发育和突触功能活性依赖的调节过程中，突触后致密蛋白磷酸化的机制仍然是未知的领域。突触后Rap GTP酶激活蛋白SPAR与PSD95结合，可以促进树突棘的生长并加强突触。Plk2（polo-like kinase2，也称为Snk）是一种受突触活性诱导表达的蛋白激酶，它可以磷酸化SPAR，磷酸化的SPAR通过泛素化．蛋白酶体途径降解，从而导致树突棘和突触的减少。Plk2的诱导表达和随后SPAR的降解是长时间神经活性增强过程中突触强度的稳态抑制（突触剥落）所必需的。有趣的是，SPAR需要被另外一种激酶cDK5磷酸化后才能被Plk2所降解。这种机制通过CDK5对一部分突触进行标记，为由Plk2-SPAR通路抑制或去除这些突触提供了可能的途径，但其分子机制在神经退行性疾病突触丢失中的作用仍需进一步探讨。

A molecular mechanism for activity-dependent synaptic suppression and synaptic homeostasis

Regulation of specific proteins by phosphorylation is usually overlooked by standard loss-of-function approaches such as RNAi or gene knockout, which simply remove the gene or protein. Phosphorylation of postsynaptic density proteins remains a largely unexplored mechanism in activity-dependent regulation of dendrite development and synaptic function. The postsynaptic Rap GTPase activating protein （RapGAP） SPAR binds to PSD-95 and it promotes spine growth and strengthens synapses. SPAR is phosphorylated by Plk2 （polo-like kinase 2; also known as Snk）, a protein kinase whose expression is induced by synaptic activity. Phosphorylation of SPAR by Plk2 leads to degradation of SPAR by the ubiquitin proteasome pathway, leading to loss of spines and synapses. Plk2 induction and subsequent SPAR degradation is required for homeostatic suppression （synaptic scaling） of synaptic strength during chronic heightened activity. Interestingly, SPAR needs to be phosphorylated （primed） by another kinase （CDK5） to be degraded by Plk2. Such a mechanism provides a potential means for CDK5 to ＂tag＂ a subset of synapses for suppression and elimination via the Plk2- SPAR pathway. The implications for this molecular pathway in synapse loss of neurodegenerative disease will be discussed.