HSP cell abnormalities

Posted - December 2016 in Research Highlights

Lipid droplet metabolism important

 

Here are two research studies investigating lipid droplet changes with HSP.

 

The first study establishes a strong link between changes in the endoplasmic reticulum (ER) and changes in lipid droplets that derive from the ER.

 

Craig Blackstone

Dr. Craig Blackstone

Mutations in the main HSP causing genes lead to alterations in the tubular network (ER – endoplasmic reticulum) in cells. This study shows that lipid droplet abnormalities occur hand-in-hand with those in ER development and structure, with important implications for the most common forms of HSP.

 

Hereditary spastic paraplegias (HSPs; SPG1-76 plus others) are length-dependent disorders affecting long corticospinal axons, and the most common autosomal dominant forms are caused by mutations in genes that encode the spastin (SPG4), atlastin-1 (SPG3A), and REEP1 (SPG31) proteins. These proteins bind one another and shape the tubular endoplasmic reticulum (ER) network throughout cells. They also are involved in lipid droplet formation, enlargement, or both in cells, though mechanisms remain unclear.

 

Here we have identified evidence of partial lipoatrophy in Reep1 null mice in addition to prominent spastic paraparesis. Furthermore, Reep1-/- embryonic fibroblasts and neurons in the cerebral cortex both show lipid droplet abnormalities. The apparent partial lipodystrophy in Reep1 null mice, although less severe, is reminiscent of the lipoatrophy phenotype observed in the most common form of autosomal recessive lipodystrophy, Berardinelli-Seip congenital lipodystrophy. Berardinelli-Seip lipodystrophy is caused by autosomal recessive mutations in the BSCL2 gene that encodes an ER protein, seipin, that is also mutated in the autosomal dominant HSP SPG17 (Silver syndrome). Furthermore, REEP1 co-immunoprecipitates with seipin in cells.

 

This strengthens the link between alterations in ER morphogenesis and lipid abnormalities, with important pathogenic implications for the most common forms of HSP.

 

SOURCE: Hum Mol Genet. 2016 Sep 16. pii: ddw315. [Epub ahead of print] Published by Oxford University Press 2016. This work is written by US Government employees and are in the public domain in the US. PMID: 27638887 DOI: 10.1093/hmg/ddw315

 

Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.

 

Renvoisé B1, Malone B1, Falgairolle M2, Munasinghe J3, Stadler J1, Sibilla C4, Park SH1, Blackstone C5.

1 Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

2 Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

3 Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

4 Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA, Present address: MRC Laboratory of Molecular Biology, Cambridge, UK.

5 Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA, [email protected]


 

The second study confirms the importance of lipid metabolism in HSP pathogenesis.

 

Prof. Elena Rugarli

Prof. Elena Rugarli

Hereditary spastic paraplegia (HSP) is a progressive neurodegenerative disease characterized by lower limb spasticity and weakness. It is caused by the dying back of the corticospinal axons in the central nervous system. Most of the autosomal dominant cases of this disease have mutations in the gene SPAST, encoding for spastin, a conserved microtubule severing protein belonging to the AAA (ATPases Associated with various cellular Activities) family. Spastin plays a role in midbody abscission, spindle disassembly, neurite branching and endosomal tubulation. Spastin is mainly present in two isoforms, M1 and M87 including or excluding an N-terminal hydrophobic region, respectively.

 

It has been shown earlier that spastin-M1 is targeted to lipid droplets upon overexpression. Lipid droplets (LDs) are intracellular organelles that originate from the ER. They contain a neutral lipid core of triacylglycerol (TAG) and cholesterol esters (CE) and a monolayer of phospholipids. In this study we generated a spastin knock-out cell line by CRISPR-Cas9 technology in NSC34 cells. We show that spastin knock-out cells upon starvation upregulated the LD-associated protein PLIN2 and the principal lipase ATGL responsible for breakdown of LDs. This was accompanied by increase in all species of TAGs and a reduction in the CE content in cells depleted of spastin. An increase in the number and size of LDs upon starvation was seen also in mouse embryonic fibroblasts (MEFs) obtained from spastin knock out mice embryos.

 

These results indicate that the absence of spastin affects lipid turnover in cells. This study, along with other recent studies implicating lipid droplet biology in HSP, strongly hints towards the importance of lipid metabolism in the pathogenesis of the disease.

 

SOURCE: International Meeting on Spastic Paraparesis and Ataxias

Paris June 2016 https://spatax.files.wordpress.com/2016/06/booklet-20161.pdf

 

The role of Spastin in Lipid Droplet metabolism and its relevance to Hereditary Spastic Paraplegia (Poster session II)

 

Nimesha Tadepalle 1, 2, Chrisovalantis Papadopoulos1, 2, Elena Rugarli1, 2, 3

1Institute for Genetics, University of Cologne, Germany

2Cologne Excellence Cluster on Cellular Stress Responses in AgingAssociated Diseases (CECAD), Cologne, Germany

3Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.

 

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