Functional screening in Drosophila reveals the conserved role of REEP1 in promoting stress resistance and preventing the formation of Tau aggregates

Appocher, Chiara; Klima, Raffaella; Feiguin, Fabián

doi:10.1093/hmg/ddu393

Cited by 16 publications

(20 citation statements)

References 55 publications

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“… 16 Recently, it was shown in a Drosophila model that overexpression of reep1 prevents tau-mediated neurodegeneration and promotes neuronal resistance to ER stress. 2 Thus, REEP1 -associated disorders may also be summarized as ER stress diseases, displaying different phenotypes depending on the type of disturbed ER function. However, the precise underlying mechanisms remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“… 1 REEP1 is associated with the mitochondria 1 and the endoplasmic reticulum (ER) and protects neurons from the accumulation of neurotoxic aggregates. 2 REEP1 mutations account for approximately 3%–10% of autosomal dominant HSPs; REEP1 is the third most frequent causative gene (following SPAST [spastin] and ATL1 [atlastin 1]). 3 , 4 More than 40 REEP1 mutations have been reported to date, comprising mainly small frameshift mutations that are all transmitted in autosomal dominant fashion.…”

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confidence: 99%

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Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy

et al. 2015

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Objective:To identify the underlying genetic cause of a congenital neuropathy in a 5-year-old boy as part of a cohort of 32 patients from 23 families with genetically unresolved neuropathies.Methods:We used autozygosity mapping coupled with next-generation sequencing to investigate a consanguineous family from Lebanon with 1 affected and 2 healthy children. Variants were investigated for segregation in the family by Sanger sequencing. A splice site mutation was further evaluated on the messenger RNA level by quantitative reverse transcription PCR. Subsequently, a larger cohort was specifically screened for receptor expression-enhancing protein 1 (REEP1) gene mutations.Results:We detected a homozygous splice donor mutation in REEP1 (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912) that cosegregated with the phenotype in the family, leading to complete skipping of exon 4 and a premature stop codon. The phenotype of the patient is similar to spinal muscular atrophy with respiratory distress type 1 (SMARD1) with additional distal arthrogryposis and involvement of the upper motor neuron manifested by pronounced hyperreflexia.Conclusion:To date, only dominant REEP1 mutations have been reported to be associated with a slowly progressive hereditary spastic paraplegia. The findings from our patient expand the phenotypical spectrum and the mode of inheritance of REEP1-associated disorders. Recessive mutations in REEP1 should be considered in the molecular genetic workup of patients with a neuromuscular disorder resembling SMARD1, especially if additional signs of upper motor neuron involvement and distal arthrogryposis are present.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy

et al. 2015

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“… 11 REEP1 and REEP2 (REEP1/2) are both reported to be HSP-related proteins. 8 , 12 REEP1 also plays important roles in lipid droplet formation, 13 ER stress response, 14 and ER-mitochondria contacts. 15 …”

Section: Introductionmentioning

confidence: 99%

DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling

et al. 2018

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The endoplasmic reticulum (ER) is composed of the nuclear envelope, perinuclear sheets and a peripheral tubular network. The peripheral ER and mitochondria form tight contacts at specific subdomains, which coordinate the functions of the two organelles and are required for multiple cellular processes such as Ca2+ transfer and apoptosis. However, it is largely unknown how ER morphology and ER-mitochondria signaling are dynamically regulated under different physiological or pathological conditions such as DNA damage. Here we show that the peripheral, tubular ER undergoes significant extension in response to DNA damage, and that this process is dependent on p53-mediated transcriptional activation of the ER-shaping proteins REEP1, REEP2 and EI24 (alias PIG8). This promotes the formation of ER-mitochondria contacts through EI24 and the mitochondrial outer membrane protein VDAC2, facilitates Ca2+ transfer from ER to mitochondria and promotes DNA damage-induced apoptosis. Thus, we identify a unique DNA damage response pathway involving alterations in ER morphology, ER-mitochondria signaling, and apoptosis.

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“…As previously reported, overexpressing the human REEP1 gene in Drosophila can promote the resistance of neurons to ER stress (Appocher et al, 2014). Several proteins encoded by HSP genes in addition to REEP1, including reticulon-2 protein, atlastin-1, spastin , REEP1, REEP2, the NIPA1 neuronal protein, strumpellin protein, and seipin, have been reported to be associated with the ER morphology and ER stress response (Esteves et al, 2014, Fink, 2013.…”

Section: Reep1 -/Mice Showed Increased Er Stress In Spinal Cord Motormentioning

confidence: 80%

Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia

Wang

Wei

et al. 2020

Biology Open

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Hereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases. HSPs are characterized by lower-extremity weakness and spasticity. However, there is no specific clinical treatment strategy to prevent or reverse nerve degeneration in HSPs. Mutations in receptor expression-enhancing protein 1 (REEP1) are well-recognized and relatively common causes of autosomal dominant HSPs. REEP1 modifies the endoplasmic reticulum (ER) shape, and is implicated in the ER stress response. Defects in the ER stress response seem to be crucial mechanisms underlying HSP neurodegeneration. Here, we report that REEP1−/− mice exhibit progressive motor deficits, along with denervation of neuromuscular junctions and increased ER stress. Moreover, marked axonal degeneration and morphological abnormalities are observed. In this study, we treated both REEP1−/− and wild-type (WT) mice with salubrinal, which is a specific inhibitor of ER stress, and we observed increased nerve-muscle connections and enhanced motor functions. Our data highlight the importance of ER homeostasis in HSPs, providing new opportunities for HSP treatment.

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Functional screening in Drosophila reveals the conserved role of REEP1 in promoting stress resistance and preventing the formation of Tau aggregates

Cited by 16 publications

References 55 publications

Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy

Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy

DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling

Inhibition of ER stress improves progressive motor deficits in a REEP1-null mouse model of hereditary spastic paraplegia

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