scholarly journals Defects in ER–endosome contacts impact lysosome function in hereditary spastic paraplegia

2017 ◽  
Vol 216 (5) ◽  
pp. 1337-1355 ◽  
Author(s):  
Rachel Allison ◽  
James R. Edgar ◽  
Guy Pearson ◽  
Tania Rizo ◽  
Timothy Newton ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stem Cell ◽  
Hereditary Spastic Paraplegia ◽  
Axonal Degeneration ◽  
Contact Process ◽  
Primary Neurons ◽  
Human Stem Cell ◽  
Spastic Paraplegia ◽  
Microtubule Severing ◽  
Cellular Models

Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER–endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell–derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER–endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.

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 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.

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 Chemically Induced Senescence in Human Stem Cell-Derived Neurons Promotes Phenotypic Presentation of Neurodegeneration

2021 ◽  
Author(s):  
Ali Fathi ◽  
Sakthikumar Mathivanan ◽  
Linghai Kong ◽  
Andrew J Petersen ◽  
Cole R.K Harder ◽  
...  
Keyword(s):  
Stem Cell ◽  
Small Molecules ◽  
Motor Neurons ◽  
Cortical Neurons ◽  
Axonal Degeneration ◽  
Human Stem Cell ◽  
Human Stem Cells ◽  
Embryonic Fibroblasts ◽  
Age Related ◽  
Chemically Induced

Modeling age-related neurodegenerative disorders with human stem cells is difficult due to the embryonic nature of stem cell derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the senescence cocktail was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our senescence cocktail will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.

scholarly journals Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

2016 ◽  
Vol 129 (22) ◽  
pp. 2759-2761 ◽  
Author(s):  
Wo-Tu Tian ◽  
Jun-Yi Shen ◽  
Xiao-Li Liu ◽  
Tian Wang ◽  
Xing-Hua Luan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Raft ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Novel Mutations

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
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