Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis

Namekawa, Michito; Muriel, Marie‐Paule; Janer, Alexandre; Latouche, Morwena; Dauphin, Aurélien; Debeir, Thomas; Martin, Elodie; Duyckaerts, Charles; Prigent, Annie‐France; Depienne, Christel; Sittler, Annie; Brice, Alexis; Ruberg, Merle

doi:10.1016/j.mcn.2007.01.012

Cited by 68 publications

(79 citation statements)

References 31 publications

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“…Hence, RAB6A, which is a central gene in the AD metastable network described in this work, could play an important role in the regulation of the metastable proteins by directing them toward the endosomallysosomal degradation machinery, thereby preventing their accumulation in the cytoplasm. Another two genes in the group that we found are ATP6V1H, which encodes a protein subunit of a vacuolar ATPase involved in clathrin-mediated endocytosis (57,58) and whose role in regulating lysosomal pH has been recently been linked to neurodegeneration (59), and ATL1, which is involved in ER trafficking (60,61). In fact, all 10 genes that we found to be related to trafficking are part of the endosomal-lysosomal system.…”

Section: Test Of Module Generality Using a Consensus Network Analysismentioning

confidence: 72%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

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

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Alzheimer's disease is the most common cause of dementia. A hallmark of this disease is the presence of aberrant deposits containing by the Aβ peptide (amyloid plaques) and the tau protein (neurofibrillary tangles) in the brains of affected individuals. Increasing evidence suggests that the formation of these deposits is closely associated with the age-related dysregulation of a large set of highly expressed and aggregation-prone proteins, which make up a metastable subproteome. To understand in more detail the origins of such dysregulation, we identify specific components of the protein homeostasis system associated with these metastable proteins by using a gene coexpression analysis. Our results reveal the particular importance of the protein trafficking and clearance mechanisms, including specific branches of the endosomal-lysosomal and ubiquitin-proteasome systems, in maintaining the homeostasis of the metastable subproteome associated with Alzheimer's disease.Alzheimer's disease | protein aggregation | protein homeostasis | supersaturation

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Section: Test Of Module Generality Using a Consensus Network Analysismentioning

confidence: 72%

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Kundra

Ciryam

Morimoto

et al. 2017

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

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“…For example, spartin (SPG20) has been linked to clathrin-mediated endocytosis (58), and spastin (SPG4) and ZFYVE27 (SPG33) localize to endosomes and are thought to function in intracellular trafficking (59 -61). Perhaps most relevant to this study is the transmembrane GTPase atlastin 1 (SPG3A), which is localized to the cis-Golgi and the ERGIC (62)(63)(64). Interestingly, expression of atlastin 1 with various disease mutations disrupts either vesicle budding at the ER or the transport of ER vesicles to the Golgi (62) and leads to alterations in ER morphology and Golgi structure (63,64).…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps most relevant to this study is the transmembrane GTPase atlastin 1 (SPG3A), which is localized to the cis-Golgi and the ERGIC (62)(63)(64). Interestingly, expression of atlastin 1 with various disease mutations disrupts either vesicle budding at the ER or the transport of ER vesicles to the Golgi (62) and leads to alterations in ER morphology and Golgi structure (63,64). However, no studies have yet linked the COPI pathway to neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Scyl1, Mutated in a Recessive Form of Spinocerebellar Neurodegeneration, Regulates COPI-mediated Retrograde Traffic

Burman

Bourbonnière

Philie

et al. 2008

Journal of Biological Chemistry

111

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Scy1-like 1 (Scyl1), a member of the Scy1-like family of catalytically inactive protein kinases, was recently identified as the gene product altered in muscle-deficient mice, which suffer from motor neuron degeneration and cerebellar atrophy. To determine the function of Scyl1, we have now used a mass spectrometry-based screen to search for Scyl1-binding partners and identified components of coatomer I (COPI) coats. The interaction was confirmed in pull-down assays, and Scyl1 co-immunoprecipitates with ␤COP from brain lysates. Interestingly, and unique for a non-transmembrane domain protein, Scyl1 binds COPI coats using a C-terminal RKLD-COO ؊ sequence, similar to the KKXX-COO ؊ COPI-binding motif found in transmembrane endoplasmic reticulum (ER) proteins. Scyl1 co-localizes with ␤COP and is localized, in an Arf1-independent manner, to the ER-Golgi intermediate compartment and the cis-Golgi, sites of COPI-mediated membrane budding. The localization and binding properties of Scyl1 strongly suggest a function in COPI transport, and inhibitory RNA-mediated knock down of the protein disrupts COPI-mediated retrograde traffic of the KDEL receptor to the ER without affecting anterograde traffic from the ER. Our data demonstrate a function for Scyl1 as an accessory factor in COPI trafficking and suggest for the first time that alterations in the COPI pathway result in neurodegenerative disease.The murine autosomal recessive neurodegenerative disease model "muscle-deficient" (mdf) displays clinical and histological features indicative of a progressive motor neuropathy (1). Homozygotes develop a posterior waddle at 4 -8 weeks of age followed by hind limb paralysis and forelimb weakness (1). Skeletal muscles exhibit a neurogenic atrophy, and there is progressive neurodegeneration of lower motor neurons (1, 2). Among the murine neuromuscular atrophies, the motor neuron degeneration in mdf is most similar to that seen in wobbler (1). Interestingly, mdf also suffers from symptoms indicative of cerebellar involvement including gait ataxia, abnormal hind limb posture, and tremor (3). Therefore, mdf appears to be linked to both neuromuscular atrophy and spinocerebellar ataxia and is thus an animal model for neuromuscular disease with cerebellar involvement in humans.Most recently, null mutations in the Scy1-like 1 (Scyl1) gene were determined to be responsible for the pathology seen in the mdf mouse (3). Scyl1 was initially identified as a ubiquitously expressed member of the Scy1-like family of protein kinases (4) and is a distant homologue of Scy1-like 2/CVAK104 (coated vesicle-associated kinase of 104 kDa), which is involved in the trafficking of clathrin-coated vesicles (CCVs) 3 (5-7). Scy1-like kinases are thought to be kinase-inactive as they lack several highly conserved residues essential for catalytic activity (8, 9). Scyl1 was indirectly implicated in clathrin-mediated endocytosis when it was identified as an in vitro binding partner for the ␣-and ␤2-ear domains of the clathrin adaptor protein-2 (AP-2) (in this study, ...

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“…In fact, the Golgi apparatus is fragmented when atlastin is depleted in some Drosophila and mammalian cells, though secretory function is largely preserved, as well as upon REEP1 overexpression (present study and refs. 9,48,51). In these cases, the microtubule network is also disrupted.…”

Section: Figurementioning

confidence: 99%

Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network

Park

Zhu²,

Parker³

et al. 2010

J. Clin. Invest.

337

493

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Hereditary spastic paraplegias (HSPs; SPG1-45) are inherited neurological disorders characterized by lower extremity spastic weakness. More than half of HSP cases result from autosomal dominant mutations in atlastin-1 (also known as SPG3A), receptor expression enhancing protein 1 (REEP1; SPG31), or spastin (SPG4). The atlastin-1 GTPase interacts with spastin, a microtubule-severing ATPase, as well as with the DP1/Yop1p and reticulon families of ER-shaping proteins, and SPG3A caused by atlastin-1 mutations has been linked pathogenically to abnormal ER morphology. Here we investigated SPG31 by analyzing the distribution, interactions, and functions of REEP1. We determined that REEP1 is structurally related to the DP1/Yop1p family of ER-shaping proteins and localizes to the ER in cultured rat cerebral cortical neurons, where it colocalizes with spastin and atlastin-1. Upon overexpression in COS7 cells, REEP1 formed protein complexes with atlastin-1 and spastin within the tubular ER, and these interactions required hydrophobic hairpin domains in each of these proteins. REEP proteins were required for ER network formation in vitro, and REEP1 also bound microtubules and promoted ER alignment along the microtubule cytoskeleton in COS7 cells. A SPG31 mutant REEP1 lacking the C-terminal cytoplasmic region did not interact with microtubules and disrupted the ER network. These data indicate that the HSP proteins atlastin-1, spastin, and REEP1 interact within the tubular ER membrane in corticospinal neurons to coordinate ER shaping and microtubule dynamics. Thus, defects in tubular ER shaping and network interactions with the microtubule cytoskeleton seem to be the predominant pathogenic mechanism of HSP.

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Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis

Cited by 68 publications

References 31 publications

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

Scyl1, Mutated in a Recessive Form of Spinocerebellar Neurodegeneration, Regulates COPI-mediated Retrograde Traffic

Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network

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