HSP-impaired cell functions studied

Posted - June 2012 in Research Highlights

Importance of Reticulon protein demonstrated

 

An HSP gene, reticulon (SPG12) has been shown to be important in the organisation and function of smooth endoplasmic reticulum (ER), a critical component of cells, in the furthest ends of long nerve fibres of fruit flies.

 

The study sheds light on the role of the smooth ER in the longer motor axons (long arms of nerve cells of the brain and spinal cord), and what happens when the reticulon gene is mutated. Low levels of reticulon are associated with axonal degeneration, a characteristic feature of HSP.

 

Background

Several causative genes for hereditary spastic paraplegia encode proteins with intramembrane hairpin loops that contribute to curvature of the endoplasmic reticulum (ER), but the relevance of this function to axonal degeneration is not understood. One of these genes is reticulon2. In contrast to mammals, Drosophila has only one widely expressed reticulon ortholog, Rtnl1, and we therefore used Drosophila to test its importance for ER organization and axonal function.

 

Results

Rtnl1 distribution overlapped with that of ER, but in contrast to rough ER, was enriched in axons. Loss of Rtnl1 led to expansion of rough or sheet ER in larval epidermis and elevated levels of ER stress. It also caused abnormalities specifically within distal portions of longer motor axons and in their presynaptic terminals, including disruption of smooth ER, the microtubule cytoskeleton, and mitochondria. In contrast proximal axon portions appeared unaffected.

 

Conclusions

Our results provide direct evidence for reticulon function in organization of smooth ER in distal longer axons, and support a model in which spastic paraplegia can be caused by impairment of axonal smooth ER. Our data provide a route to further understanding of both the role of smooth ER in axons, and the pathological consequences of impairment of this compartment.

 

SOURCE:  Hum. Mol. Genet. (2012) doi: 10.1093/hmg/dds167   First published online:  April 27, 2012

 

Reticulon-like-1, the Drosophila ortholog of the Hereditary Spastic Paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons

 

Niamh C. O’Sullivan1,*, Thomas R Jahn1, Evan Reid2 and Cahir J. O’Kane1,*

 

1Department of Genetics, University of Cambridge, United Kingdom

2Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, United Kingdom

 

 

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