Mutations in the Novel Mitochondrial Protein REEP1 Cause Hereditary Spastic Paraplegia Type 31

Züchner, Stephan; Wang, Gaofeng; Tran-Viet, Khanh-Nhat; Nance, Martha; Gaskell, P. C.; Vance, Jeffery M.; Ashley-Koch, Allison E.; Pericak‐Vance, Margaret A.

doi:10.1086/505361

Cited by 221 publications

(211 citation statements)

References 15 publications

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“…REEP members such as REEP5, a member of the DP1 family, regulate intracellular trafficking by affecting ER membrane structure and cargo capacity and by acting as adapter proteins 12. Contrasting findings regarding the intracellular localization and mechanisms of action of the REEP proteins have been described 20, 21. The present findings expand our understanding of REEP5 as a molecule that shapes the ER.…”

Section: Discussionmentioning

confidence: 55%

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Yao

Xie

et al. 2018

JAHA

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BackgroundHeart failure is a complex syndrome characterized by cardiac contractile impairment with high mortality. Defective intracellular Ca2+ homeostasis is the central cause under this scenario and tightly links to ultrastructural rearrangements of sarcolemmal transverse tubules and the sarcoplasmic reticulum (SR); however, the modulators of the SR architecture remain unknown. The SR has been thought to be a specialized endoplasmic reticulum membrane system. Receptor accessory proteins (REEPs)/DP1/Yop1p are responsible for shaping high‐curvature endoplasmic reticulum tubules. This study aimed to determine the role of REEPs in SR membrane shaping and thus cardiac function.Methods and ResultsWe identified REEP5 (receptor accessory protein 5) as more highly expressed than other REEP members in adult rat ventricular myocardium, and it was downregulated in the failing hearts. Targeted inactivation of REEP5 in rats specially deformed the cardiac SR membrane without affecting transverse tubules, and this was visualized by focused ion beam scanning electron microscopy–based 3‐dimensional reconstruction. Accordingly, simultaneous recordings of depolarization‐induced Ca2+ currents and Ca2+ transients in REEP5‐null cardiomyocytes revealed normal L‐type Ca2+ channel currents but a depressed SR Ca2+ release. Consequently, the excitation–contraction coupling gain of cardiomyocytes and consequent cardiac contractility were compromised. REEP5 deficiency did not alter the expression of major proteins involved in Ca2+ handling in the heart.Conclusions REEP5 modulates cardiac function by shaping the SR. REEP5 defect deforms the SR architecture to depress cardiac contractility. REEP5‐dependent SR shaping might have potential as a therapeutic target for heart failure.

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Section: Discussionmentioning

confidence: 55%

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Yao

Xie

et al. 2018

JAHA

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“…Similarly, mutations in ATL1 have been linked to pure HSP, but can also result in motor neuropathy with sensory involvement (45)(46)(47). In the case of REEP1, distinct mutations have been shown to give rise to defects that affect only upper motoneurons (22) or only lower motoneurons (48), similar to the disparate effects of the two unique mutations identified in TFG. Strikingly, all these factors function at the ER.…”

Section: Resultsmentioning

confidence: 90%

“…Depletion of atlastin-1 perturbs ER structure and has been shown to inhibit axon elongation in rat cortical neurons (20,21). REEP1 mutations also cause an uncomplicated form of HSP (22). Together with reticulons, which have also been implicated in HSP (23), members of the REEP family are thought to generate and/or maintain the highly curved shape of ER membranes (7).…”

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confidence: 99%

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Beetz

Johnson

Schuh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

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“…The importance of REEPs in ER morphology is also highlighted by their implication in human diseases that are associated with neurons having long axons and requiring an extended tubular ER (9,10). For example, mutations in the transmembrane domain of REEP1, which is primarily expressed in neurons (11), lead to pure forms of hereditary spastic paraplegia (HSP) (12,13).…”

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confidence: 99%

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

Brady

Claridge

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The integral membrane proteins of the DP1 (deleted in polyposis) and reticulon families are responsible for maintaining the high membrane curvature required for both smooth endoplasmic reticulum (ER) tubules and the edges of ER sheets, and mutations in these proteins lead to motor neuron diseases, such as hereditary spastic paraplegia. Reticulon/DP1 proteins contain reticulon homology domains (RHDs) that have unusually long hydrophobic segments and are proposed to adopt intramembrane helical hairpins that stabilize membrane curvature. We have characterized the secondary structure and dynamics of the DP1 family protein produced from the YOP1 gene (Yop1p) and identified a C-terminal conserved amphipathic helix (APH) that, on its own, interacts strongly with negatively charged membranes and is necessary for membrane tubule formation. Analyses of DP1 and reticulon family members indicate that most, if not all, contain C-terminal sequences capable of forming APHs. Together, these results indicate that APHs play a previously unrecognized role in RHD membrane curvature stabilization.T he endoplasmic reticulum (ER) is the largest membranebound organelle in the eukaryotic cell and adopts diverse morphologies, including tubules that extend outward to the cell periphery and sheet-like structures closer to the nucleus (1, 2). The regions of high membrane curvature that are found in the ER tubules and sheets are stabilized by the DP1 (deleted in polyposis) and reticulon classes of integral membrane proteins (3-5). Consistent with their role in ER morphology, similar proteins have not been found in prokaryotes (6).There are six human DP1 proteins originally identified as accessory proteins facilitating the expression of odorant receptors, and thus termed receptor expression-enhancing proteins (REEPs) (7). The ability of REEPs to facilitate receptor trafficking has recently been related back to their ER shaping activities (8). The importance of REEPs in ER morphology is also highlighted by their implication in human diseases that are associated with neurons having long axons and requiring an extended tubular ER (9, 10). For example, mutations in the transmembrane domain of REEP1, which is primarily expressed in neurons (11), lead to pure forms of hereditary spastic paraplegia (HSP) (12, 13).The reticulon family in humans comprises four members, Rtn1-Rtn4 (6). Rtn4 is of particular interest because it is primarily responsible for generating or stabilizing the tubular ER in mammalian cells. Rtn4 is critical in neuronal cell processes because it inhibits spontaneous neurite outgrowth (14) and restricts neuronal plasticity (15), and it has been implicated in several neural diseases, including schizophrenia and motor neuron disease (16-18).The DP1 and reticulon proteins have in common a region containing two, unusually long hydrophobic segments (≈35 aa in length each) known as a reticulon homology domain (RHD) (6). In humans, REEPs 1-6 are similar overall; however, the RHD of REEPs 1-4 is truncated (Fig. S1). REEPs 1-4 also possess...

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Mutations in the Novel Mitochondrial Protein REEP1 Cause Hereditary Spastic Paraplegia Type 31

Cited by 221 publications

References 15 publications

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

REEP5 (Receptor Accessory Protein 5) Acts as a Sarcoplasmic Reticulum Membrane Sculptor to Modulate Cardiac Function

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

A conserved amphipathic helix is required for membrane tubule formation by Yop1p

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