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.

scholarly journals Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia

2003 ◽  
Vol 163 (4) ◽  
pp. 777-787 ◽  
Author(s):  
Luigia Atorino ◽  
Laura Silvestri ◽  
Mirko Koppen ◽  
Laura Cassina ◽  
Andrea Ballabio ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Complex I ◽  
Oxidant Stress ◽  
Cellular Level ◽  
Spastic Paraplegia ◽  
Functional Conservation ◽  
Homologous Protein ◽  
Mitochondrial Inner Membrane ◽  
Increased Sensitivity ◽  
Complex I Activity

Mmutations in paraplegin, a putative mitochondrial metallopeptidase of the AAA family, cause an autosomal recessive form of hereditary spastic paraplegia (HSP). Here, we analyze the function of paraplegin at the cellular level and characterize the phenotypic defects of HSP patients' cells lacking this protein. We demonstrate that paraplegin coassembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. These two proteins form a high molecular mass complex, which we show to be aberrant in HSP fibroblasts. The loss of this complex causes a reduced complex I activity in mitochondria and an increased sensitivity to oxidant stress, which can both be rescued by exogenous expression of wild-type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin–AFG3L2 complex with the yeast m-AAA protease and assign proteolytic activity to this structure. These results shed new light on the molecular pathogenesis of HSP and functionally link AFG3L2 to this neurodegenerative disease.

scholarly journals Functional conservation of human Spastin in a Drosophila model of autosomal dominant-hereditary spastic paraplegia

2010 ◽  
Vol 19 (10) ◽  
pp. 1883-1896 ◽  
Author(s):  
Fang Du ◽  
Emily F. Ozdowski ◽  
Ingrid K. Kotowski ◽  
Douglas A. Marchuk ◽  
Nina Tang Sherwood
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Spastic Paraplegia ◽  
Functional Conservation ◽  
Drosophila Model

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 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.

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