Axonal degeneration in HSP

Posted - June 2017 in Research Highlights

Link between different classes of HSP proteins

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Evan Reid

A multinational team led by eminent HSP researcher Evan Reid of Cambridge University in England have completed a study suggesting a functional link between different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration.

 

Abstract

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.

 

SOURCE: J Cell Biol. 2017 May 1;216(5):1337-1355. doi: 10.1083/jcb.201609033. Epub 2017 Apr 7. PMID: 28389476 © 2017 Allison et al.

 

Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.

 

Allison R1,2, Edgar JR1,3, Pearson G1,2, Rizo T4, Newton T1,2, Günther S5, Berner F1, Hague J1,2, Connell JW1,2, Winkler J6, Lippincott-Schwartz J7, Beetz C5, Winner B4,8, Reid E9,2.

 

1 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK.

2 Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, England, UK.

3 Department of Clinical Biochemistry, University of Cambridge, Cambridge CB2 0XY, England, UK.

4 Interdisciplinary Center for Clinical Research (IZKF) Junior Research Group III and Federal Ministry of Education and Research (BMBF) Research Group Neuroscience, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.

5 Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, 07743 Jena, Germany.

6 Department of Molecular Neurology, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.

7 Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.

8 Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuernberg, 91054 Erlangen, Germany.

9 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK [email protected]

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