Protrudin-deficient mice manifest depression-like behavior with abnormalities in activity, attention, and cued fear-cond
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RESEARCH
Protrudin‑deficient mice manifest depression‑like behavior with abnormalities in activity, attention, and cued fear‑conditioning Michiko Shirane1*, Hirotaka Shoji2, Yutaka Hashimoto3, Hiroyuki Katagiri4, Shizuka Kobayashi4, Toshiya Manabe4, Tsuyoshi Miyakawa2 and Keiichi I. Nakayama3*
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. Keywords: Protrudin, Knockout mouse, Behavior, Hyperactivity, Depression Introduction Protrudin is an endoplasmic reticulum (ER)–resident protein that promotes neurite formation through regulation of endosome trafficking [1–8]. We have recently shown that protrudin and its binding partner PDZD8 cooperatively play an important role in the development of neuronal polarity and maintenance of neuronal integrity by mediating the tethering of endosomes to ER and consequent lipid transfer at the membrane contact sites that is essential for endosome maturation [9–11]. Loss of protrudin or PDZD8 thus impairs the establishment of *Correspondence: [email protected]‑cu.ac.jp; [email protected]‑u.ac.jp 1 Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan 3 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan Full list of author information is available at the end of the article
neuronal polarity and gives rise to neurodegeneration in association with compromised endosome maturation. Mutations of the human protrudin gene—ZFYVE27, also 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 [12–16]. 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 [17–21]. Given that
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