Role of Spastin & cognitive dysfunction in HSP

Understanding of Interaction with AMPAR receptor advanced

Mice with Spastin depletion exhibit working* and associated memory** deficits related to reduced AMPAR receptor levels that are essential for proper functioning of nerve synapses. This study shows that Spastin importantly interacts with AMPAR, independent of microtubule dynamics.

* Working memory is a cognitive system with a limited capacity that can hold information temporarily.[1] Working memory is important for reasoning and the guidance of decision-making and behavior.

** Associative memory is defined as the ability to learn and remember the relationship between unrelated items. This would include, for example, remembering someone’s name.


Synaptic plasticity is essential for cognitive functions such as learning and memory. One of the mechanisms involved in synaptic plasticity is the dynamic delivery of AMPA receptors (AMPARs) in and out of synapses.

Mutations of SPAST, which encodes SPASTIN, a microtubule-severing protein, are considered the most common cause of hereditary spastic paraparesis (HSP). In some cases, patients with HSP also manifest cognitive impairment. In addition, mice with Spastin depletion exhibit working and associative memory deficits and reduced AMPAR levels. However, the exact effect and molecular mechanism of Spastin on AMPARs trafficking has remained unclear.

Here, we report that Spastin interacts with AMPAR, and phosphorylation of Spastin enhances its interaction with AMPAR subunit GluA2. Further study shows that phosphorylation of Spastin can increase AMPAR GluA2 surface expression and the amplitude and frequency of miniature excitatory synaptic currents (mEPSC) in cultured hippocampal neurons. Moreover, phosphorylation of Spastin at Ser210 is crucial for GluA2 surface expression. Phosphorylation of Spastin K353A, which obliterates microtubule-severing activity, also promotes AMPAR GluA2 subunit trafficking to the surface and increases the amplitude and frequency of mEPSCs in cultured neurons.

Taken together, our data demonstrate that Spastin phosphorylation promotes the surface delivery of the AMPAR GluA2 subunit independent of microtubule dynamics.

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SOURCE:  Front Cell Neurosci. 2022; 16: 809934. Published online 2022 Mar 28. doi: 10.3389/fncel.2022.809934 PMID: 35418834

Phosphorylation of Spastin Promotes the Surface Delivery and Synaptic Function of AMPA Receptors

Li Chen, 1 , Hanjie Wang, 1 , Shuhan Cha, 1 , Jiong Li, 1 Jiaqi Zhang, 1 Jiaming Wu, 1 , 2 Guoqing Guo, 1 , * and Jifeng Zhang 1 , *

1. Department of Anatomy, Neuroscience Laboratory for Cognitive and Developmental Disorders, Medical College of Jinan University, Guangzhou, China

2. Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou, China

Corresponding author.

These authors have contributed equally to this work

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