Abstract
The membrane protein seizure 6–like (SEZ6L) is a neuronal substrate of the Alzheimer’s disease protease BACE1, and little is known about its physiological function in the nervous system. Here, we show that SEZ6L constitutive knockout mice display motor phenotypes in adulthood, including changes in gait and decreased motor coordination. Additionally, SEZ6L knockout mice displayed increased anxiety-like behaviour, although spatial learning and memory in the Morris water maze were normal. Analysis of the gross anatomy and proteome of the adult SEZ6L knockout cerebellum did not reveal any major differences compared to wild type, indicating that lack of SEZ6L in other regions of the nervous system may contribute to the phenotypes observed. In summary, our study establishes physiological functions for SEZ6L in regulating motor coordination and curbing anxiety-related behaviour, indicating that aberrant SEZ6L function in the human nervous system may contribute to movement disorders and neuropsychiatric diseases.
Highlights
The protease β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1; known as β-secretase) has fundamental functions in the nervous system, both under physiological and pathophysiological conditions
We found that seizure 6–like (SEZ6L) deficiency did not lead to major anatomical or proteomic changes in the cerebellum, it is important to note that the cerebellum is only one of several anatomical structures involved in motor control
A clear difference was seen in exploratory behaviour across genotypes; the time spent moving by SEZ6L KO mice in this 3-min test was approximately half the time spent moving by WTs, and SEZ6L het mice displayed a level of movement part way between the SEZ6L KO and WT groups
Summary
The protease β-site APP cleaving enzyme 1 (BACE1; known as β-secretase) has fundamental functions in the nervous system, both under physiological and pathophysiological conditions. The molecular basis of the side effects is largely unknown, but they may result from too strongly inhibiting the cleavage of one or more of the numerous BACE1 substrates [8]. This issue needs to be resolved before clinical trials with BACE inhibitors are resumed. Given the strong expression of SEZ6L in the cerebellum, which contributes to motor coordination, SEZ6L may be involved in motor control in mice. Mice lacking all three SEZ6 family members (SEZ6 triple knockout (KO) or TKO mice) have motor coordination deficits on the rotarod and cognitive deficits [17, 18]. The lack of SEZ6L does induce specific deficits in motor functions as well as altered stress-responsive behaviour, memory functions are not affected
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