Protrudin-deficient mice manifest depression-like behavior with abnormalities in activity, attention, and cued fear-conditioning

Michiko Shirane,Toshiya Manabe,Yutaka Hashimoto,Hirotaka Shoji,Tsuyoshi Miyakawa,Keiichi I Nakayama,Shizuka Kobayashi,Hiroyuki Katagiri

doi:10.1186/s13041-020-00693-3

Abstract

Protrudin is a protein that resides in the membrane of the endoplasmic reticulum and is highly expressed in the nervous system. Although mutations in the human protrudin gene (ZFYVE27, also known as SPG33) give rise to hereditary spastic paraplegia (HSP), the physiological role of the encoded protein has been largely unclear. We therefore generated mice deficient in protrudin and subjected them to a battery of behavioral tests designed to examine their intermediate phenotypes. The protrudin-deficient mice were found to have a reduced body size and to manifest pleiotropic behavioral abnormalities, including hyperactivity, depression-like behavior, and deficits in attention and fear-conditioning memory. They exhibited no signs of HSP, however, consistent with the notion that HSP-associated mutations of protrudin may elicit neural degeneration, not as a result of a loss of function, but rather as a result of a gain of toxic function. Overall, our results suggest that protrudin might play an indispensable role in normal neuronal development and behavior.

Highlights

Protrudin is an endoplasmic reticulum (ER)–resident protein that promotes neurite formation through regulation of endosome trafficking [1,2,3,4,5,6,7,8]
Given that most individuals with hereditary spastic paraplegia (HSP) are heterozygous for mutations of SPGs that are inherited in a dominant manner, mere loss of function of the encoded proteins may not account for disease pathogenesis
Our results indicate that the PRT–/– mice have a reduced body size, show increased activity, being hyperactive in a familiar environment, as well as manifest reduced goal-directed behavior, an attenuated startle response to a sound stimulus, an attention deficit, impaired fear-conditioning memory, and increased depression-like behavior compared with WT mice

Summary

Introduction

Protrudin is an endoplasmic reticulum (ER)–resident protein that promotes neurite formation through regulation of endosome trafficking [1,2,3,4,5,6,7,8]. Loss of protrudin or PDZD8 impairs the establishment of Mutations of the human protrudin gene—ZFYVE27, known as SPG33 (spastic paraplegia gene 33)—give rise to hereditary spastic paraplegia (HSP), an axonopathy characterized by progressive spasticity and weakness of the lower limbs due to degeneration of the long axons of corticospinal tract motor neurons [12,13,14,15,16]. Most HSPcausative genes encode proteins that interact with each other and which harbor a hairpin domain that wedges in the ER membrane and increases its curvature, resulting in formation of the tubular ER network [17,18,19,20,21]. We previously showed that expression of the G191V mutant of protrudin, which has been identified in a subset of HSP

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Conclusion