Cargando…

Rare disease models provide insight into inherited forms of neurodegeneration

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been as...

Descripción completa

Detalles Bibliográficos
Autores principales: Fowler, Philippa C., Byrne, Dwayne J., O’Sullivan, Niamh C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462091/
https://www.ncbi.nlm.nih.gov/pubmed/28603788
_version_ 1783242433024229376
author Fowler, Philippa C.
Byrne, Dwayne J.
O’Sullivan, Niamh C.
author_facet Fowler, Philippa C.
Byrne, Dwayne J.
O’Sullivan, Niamh C.
author_sort Fowler, Philippa C.
collection PubMed
description Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.
format Online
Article
Text
id pubmed-5462091
institution National Center for Biotechnology Information
language English
publishDate 2016
record_format MEDLINE/PubMed
spelling pubmed-54620912017-06-07 Rare disease models provide insight into inherited forms of neurodegeneration Fowler, Philippa C. Byrne, Dwayne J. O’Sullivan, Niamh C. J Rare Dis Res Treat Article Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders. 2016 /pmc/articles/PMC5462091/ /pubmed/28603788 Text en http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 International License. (http://creativecommons.org/licenses/by/4.0)
spellingShingle Article
Fowler, Philippa C.
Byrne, Dwayne J.
O’Sullivan, Niamh C.
Rare disease models provide insight into inherited forms of neurodegeneration
title Rare disease models provide insight into inherited forms of neurodegeneration
title_full Rare disease models provide insight into inherited forms of neurodegeneration
title_fullStr Rare disease models provide insight into inherited forms of neurodegeneration
title_full_unstemmed Rare disease models provide insight into inherited forms of neurodegeneration
title_short Rare disease models provide insight into inherited forms of neurodegeneration
title_sort rare disease models provide insight into inherited forms of neurodegeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462091/
https://www.ncbi.nlm.nih.gov/pubmed/28603788
work_keys_str_mv AT fowlerphilippac rarediseasemodelsprovideinsightintoinheritedformsofneurodegeneration
AT byrnedwaynej rarediseasemodelsprovideinsightintoinheritedformsofneurodegeneration
AT osullivanniamhc rarediseasemodelsprovideinsightintoinheritedformsofneurodegeneration