Protrudin Regulates Endoplasmic Reticulum Morphology and Function Associated with the Pathogenesis of Hereditary Spastic Paraplegia

Hashimoto, Yutaka; Shirane, Michiko; Matsuzaki, Fumiko; Saita, Shotaro; Ohnishi, Takafumi; Nakayama, Keiichi I.

doi:10.1074/jbc.m113.528687

Cited by 55 publications

(75 citation statements)

References 39 publications

(46 reference statements)

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“…The protrudin gene has been found to be mutated in a subset of individuals with the autosomal dominant form of hereditary spastic paraplegia (AD-HSP), which is characterized by selective degeneration of axons4142. Protrudin interacts with Rab11, KIF5, and VAP, all of which are associated with vesicular trafficking25262728.…”

Section: Discussionmentioning

confidence: 99%

SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth

Ohnishi

Shirane

Nakayama

2017

Sci Rep

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Alternative splicing gives rise to diversity of the proteome, and it is especially prevalent in the mammalian nervous system. Indeed, many factors that control the splicing process govern nervous system development. Among such factors, SRRM4 is an important regulator of aspects of neural differentiation including neurite outgrowth. The mechanism by which SRRM4 regulates neurite outgrowth has remained poorly understood, however. We now show that SRRM4 regulates the splicing of protrudin gene (Zfyve27) transcripts in neuronal cells. SRRM4 was found to promote splicing of protrudin pre-mRNA so as to include a microexon (exon L) encoding seven amino acids in a neuron-specific manner. The resulting protein (protrudin-L) promotes neurite outgrowth during neurogenesis. Depletion of SRRM4 in Neuro2A cells impaired inclusion of exon L in protrudin mRNA, resulting in the generation of a shorter protein isoform (protrudin-S) that is less effective at promoting neurite extension. SRRM4 was found to recognize a UGC motif that is located immediately upstream of exon L and is necessary for inclusion of exon L in the mature transcript. Deletion of exon L in Neuro2A or embryonic stem cells inhibited neurite outgrowth. Our results suggest that SRRM4 controls neurite outgrowth through regulation of alternative splicing of protrudin transcripts.

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Section: Discussionmentioning

confidence: 99%

SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth

Ohnishi

Shirane

Nakayama

2017

Sci Rep

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“…The ER stress response underlies numerous adult and paediatric neurodegenerative diseases such as Parkinson's disease (PD) [42], Alzheimer's disease (AD) [43], amyotrophic lateral sclerosis [44], polyglutamine diseases [45], as well as paediatric disorders such as lysosomal storage diseases (LSD) and hereditary spastic paraplegia (HSP) [46].…”

Section: Introductionmentioning

confidence: 99%

NCLs and ER: A stressful relationship

Marotta¹,

Tinelli²,

Mole³

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders with variable age of onset, characterized by the lysosomal accumulation of autofluorescent ceroid lipopigments. The endoplasmic reticulum (ER) is a critical organelle for normal cell function. Alteration of ER homeostasis leads to accumulation of misfolded protein in the ER and to activation of the unfolded protein response. ER stress and the UPR have recently been linked to the NCLs. In this review, we will discuss the evidence for UPR activation in the NCLs, and address its connection to disease pathogenesis. Further understanding of ER-stress response involvement in the NCLs may encourage development of novel therapeutical agents targeting these pathogenic pathways.

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“…These findings are consistent with the emerging view that ER lipid metabolism is critical for long-term axonal maintenance. Despite these strong lines of evidence, further studies are required to describe the exact mechanisms underlying the interaction between CPT1C with other ER-associated proteins, such as atlastin-1 and protruding [90,104], and to determine how CPT1C alters LD expansion and size.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…In addition to atlastin-1, CPT1C has been also identified as a potential protein associated with protrudin (SPG33) [98], another ER protein that interacts with atlastin-1 and whose gene is mutated in several HSP patients [99].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

105

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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Protrudin Regulates Endoplasmic Reticulum Morphology and Function Associated with the Pathogenesis of Hereditary Spastic Paraplegia

Cited by 55 publications

References 39 publications

SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth

SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth

NCLs and ER: A stressful relationship

Carnitine palmitoyltransferase 1C: From cognition to cancer

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