scholarly journals Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

2016 ◽  
Author(s):  
Belgin Yalçın ◽  
Lu Zhao ◽  
Martin Stofanko ◽  
Niamh C O’Sullivan ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Peripheral Nerves ◽  
Hereditary Spastic Paraplegia ◽  
Membrane Curvature ◽  
Degenerative Disease ◽  
Spastic Paraplegia ◽  
Partial Loss ◽  
Form And Function ◽  
Rough Er ◽  
And Function

AbstractAxons contain an endoplasmic reticulum (ER) network that is largely smooth and tubular, thought to be continuous with ER throughout the neuron, and distinct in form and function from rough ER; the mechanisms that form this continuous network in axons are not well understood. Mutations affecting proteins of the reticulon or REEP families, which contain intramembrane hairpin domains that can model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). Here, we show that these proteins are required for modeling the axonal ER network in Drosophila. Loss of reticulon or REEP proteins can lead to expansion of ER sheets, and to partial loss of ER from distal motor axons. Ultrastructural analysis reveals an extensive ER network in every axon of peripheral nerves, which is reduced in larvae that lack reticulon and REEP proteins, with defects including larger and fewer tubules, and occasional gaps in the ER network, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of the axonal ER network, suggesting an important role for ER modeling in axon maintenance and function.

scholarly journals Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Belgin Yalçın ◽  
Lu Zhao ◽  
Martin Stofanko ◽  
Niamh C O'Sullivan ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Membrane Curvature ◽  
Degenerative Disease ◽  
Ultrastructural Analysis ◽  
Motor Axons ◽  
Spastic Paraplegia ◽  
Partial Loss ◽  
And Function ◽  
Tubular Endoplasmic Reticulum

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

scholarly journals Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

2012 ◽  
Vol 91 (6) ◽  
pp. 1051-1064 ◽  
Author(s):  
Christelle Tesson ◽  
Magdalena Nawara ◽  
Mustafa A.M. Salih ◽  
Rodrigue Rossignol ◽  
Maha S. Zaki ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Metabolizing Enzymes ◽  
Form And Function ◽  
And Function

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

2014 ◽  
Vol 289 (19) ◽  
pp. 12946-12961 ◽  
Author(s):  
Yutaka Hashimoto ◽  
Michiko Shirane ◽  
Fumiko Matsuzaki ◽  
Shotaro Saita ◽  
Takafumi Ohnishi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
And Function

scholarly journals Hereditary spastic paraplegia associated with a rare endoplasmic reticulum lipid raft-associated protein 2 mutation

2020 ◽  
Vol 7 (10) ◽  
pp. 2077
Author(s):  
Sai Chandar Dudipala ◽  
Naveen Reddy Cheruku ◽  
Krishna Chaithanya Battu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cerebral Palsy ◽  
Lipid Raft ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Recessive ◽  
Adult Population ◽  
Complex Form ◽  
Spastic Paraplegia ◽  
Childhood Onset ◽  
Exonic Deletion

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. It can present as pure form or complex form. It can be present from infancy to adulthood, but majority in adult population. Childhood onset HSP must be differentiated from common conditions like cerebral palsy, neurodegenerative disorders and metabolic disorders. Many patients with pediatric HSP are mistakenly diagnosed with cerebral palsy. In children with spastic paraplegia in whom no acquired cause identified, HSP should be considered. Here we diagnosed a 6-year-old boy with HSP who presented with progressive spastic paraplegia, intellectual disability, seizures, joint contractures and cataract. His genetic study revealed exonic deletion of endoplasmic reticulum lipid raft-associated protein gene, which is associated with complicated Autosomal recessive HSP 18 (SPG18). HSP 18 was rarely described in literature.

scholarly journals Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matias Wagner ◽  
Daniel P. S. Osborn ◽  
Ina Gehweiler ◽  
Maike Nagel ◽  
Ulrike Ulmer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Degradation Pathway ◽  
Therapeutic Interventions ◽  
Spastic Paraplegia ◽  
Ubiquitin E3 Ligase ◽  
Wide Range ◽  
Inositol 1,4,5 Trisphosphate ◽  
Cerebellar Ataxias ◽  
Trisphosphate Receptor

Abstract Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

scholarly journals Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3382-3397 ◽  
Author(s):  
Frédéric M Vaz ◽  
John H McDermott ◽  
Mariëlle Alders ◽  
Saskia B Wortmann ◽  
Stefan Kölker ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Membrane Lipids ◽  
Cerebellar Atrophy ◽  
Global Developmental Delay ◽  
Mrna Levels ◽  
Spastic Paraplegia ◽  
Protein Levels ◽  
And Function ◽  
Lipid Abnormalities ◽  
The Brain

Abstract CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.

Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein

Neurogenetics ◽  
2006 ◽  
Vol 7 (2) ◽  
pp. 93-103 ◽  
Author(s):  
Ashraf U. Mannan ◽  
Johann Boehm ◽  
Simone M. Sauter ◽  
Anne Rauber ◽  
Paula C. Byrne ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Endoplasmic Reticulum Protein

scholarly journals A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

2020 ◽  
Author(s):  
Weiwei Yu ◽  
Haiqiang Jin ◽  
Jianwen Deng ◽  
Ding Nan ◽  
Yining Huang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Spastic Paraplegia ◽  
Dna Isolation ◽  
Tertiary Structure ◽  
Novel Mutation ◽  
Chinese Family ◽  
Spastic Paraplegia ◽  
Whole Exome ◽  
And Function

Abstract Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and the this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

scholarly journals Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1232 ◽  
Author(s):  
Nicholas E. Karagas ◽  
Kartik Venkatachalam
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurological Diseases ◽  
Neuronal Function ◽  
Vesicle Release ◽  
Form And Function ◽  
And Function ◽  
Synaptic Vesicle Release ◽  
Activity Dependent ◽  
Ca2 Channels ◽  
Neuronal Compartments

By influencing Ca2+ homeostasis in spatially and architecturally distinct neuronal compartments, the endoplasmic reticulum (ER) illustrates the notion that form and function are intimately related. The contribution of ER to neuronal Ca2+ homeostasis is attributed to the organelle being the largest reservoir of intracellular Ca2+ and having a high density of Ca2+ channels and transporters. As such, ER Ca2+ has incontrovertible roles in the regulation of axodendritic growth and morphology, synaptic vesicle release, and neurotransmission activity dependent gene expression, synaptic plasticity, and mitochondrial bioenergetics. Not surprisingly, many neurological diseases arise from ER Ca2+ dyshomeostasis, either directly due to alterations in ER resident proteins, or indirectly via processes that are coupled to the regulators of ER Ca2+ dynamics. In this review, we describe the mechanisms involved in the establishment of ER Ca2+ homeostasis in neurons. We elaborate upon how changes in the spatiotemporal dynamics of Ca2+ exchange between the ER and other organelles sculpt neuronal function and provide examples that demonstrate the involvement of ER Ca2+ dyshomeostasis in a range of neurological and neurodegenerative diseases.

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