scholarly journals An ESCRT–spastin interaction promotes fission of recycling tubules from the endosome

2013 ◽  
Vol 202 (3) ◽  
pp. 527-543 ◽  
Author(s):  
Rachel Allison ◽  
Jennifer H. Lumb ◽  
Coralie Fassier ◽  
James W. Connell ◽  
Daniel Ten Martin ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Axonal Degeneration ◽  
Motor Axons ◽  
Spastic Paraplegia ◽  
Endosomal Sorting ◽  
Spinal Motor ◽  
Endosomal Recycling ◽  
Sodium Tolerance ◽  
Escrt Complex

Mechanisms coordinating endosomal degradation and recycling are poorly understood, as are the cellular roles of microtubule (MT) severing. We show that cells lacking the MT-severing protein spastin had increased tubulation of and defective receptor sorting through endosomal tubular recycling compartments. Spastin required the ability to sever MTs and to interact with ESCRT-III (a complex controlling cargo degradation) proteins to regulate endosomal tubulation. Cells lacking IST1 (increased sodium tolerance 1), an endosomal sorting complex required for transport (ESCRT) component to which spastin binds, also had increased endosomal tubulation. Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery. Spastin is mutated in the axonopathy hereditary spastic paraplegia. Zebrafish spinal motor axons depleted of spastin or IST1 also had abnormal endosomal tubulation, so we propose this phenotype is important 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 Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2238-2252 ◽  
Author(s):  
Xiang Lin ◽  
Hui-Zhen Su ◽  
En-Lin Dong ◽  
Xiao-Hong Lin ◽  
Miao Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Cortical Neurons ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Wild Type Mouse ◽  
Spastic Paraplegia ◽  
Endosomal Sorting ◽  
Hereditary Spastic Paraplegias ◽  
Cultured Cortical Neurons

Abstract Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

scholarly journals Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study

2019 ◽  
Vol 9 (10) ◽  
pp. 268 ◽  
Author(s):  
List ◽  
Kohl ◽  
Winkler ◽  
Marxreiter ◽  
Doerfler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Corpus Callosum ◽  
Hereditary Spastic Paraplegia ◽  
Axonal Degeneration ◽  
Corticospinal Tract ◽  
Disease Duration ◽  
Cervical Spinal Cord ◽  
Internal Capsule ◽  
Healthy Controls ◽  
Spastic Paraplegia

Objective: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). Methods: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. Results: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. Conclusion: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.

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 Variable and Tissue-Specific Subunit Composition of Mitochondrial m-AAA Protease Complexes Linked to Hereditary Spastic Paraplegia

2006 ◽  
Vol 27 (2) ◽  
pp. 758-767 ◽  
Author(s):  
Mirko Koppen ◽  
Metodi D. Metodiev ◽  
Giorgio Casari ◽  
Elena I. Rugarli ◽  
Thomas Langer
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Tissue Specificity ◽  
Axonal Degeneration ◽  
Protein Quality ◽  
Brain Mitochondria ◽  
Spastic Paraplegia ◽  
Substrate Specificities ◽  
Functional Conservation ◽  
Mitochondrial Inner Membrane ◽  
Different Tissues

ABSTRACT The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.

Sign in / Sign up

Export Citation Format

Share Document