Spastin regulates lipid droplet metabolism

Posted - June 2015 in Research Highlights

Lipid droplet dysfunction may cause HSP

 

SPG 4 HSP mutations involve abnormal levels of spastin protein production, either overexpression (higher than normal) or underexpression (lower than normal). These levels are linked with size and number of lipid droplets, opening the possibility that dysfunction of lipid droplets in nerve axons may contribute to how HSP is caused.

 

Mutations in SPAST, encoding spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). HSP is characterized by weakness and spasticity of the lower limbs, owing to progressive retrograde degeneration of the long corticospinal axons.

 

Spastin is a conserved microtubule (MT)-severing protein, involved in processes requiring rearrangement of the cytoskeleton in concert with membrane remodeling, such as neurite branching, axonal growth, mid-body abscission, and endosome tubulation. Two isoforms of spastin are synthesized from alternative initiation codons (M1 and M87).

 

We now show that spastin-M1 can sort from the endoplasmic reticulum (ER) to pre- and mature lipid droplets (LDs). A hydrophobic motif comprised of amino acids 57 through 86 of spastin was sufficient to direct a reporter protein to LDs, while mutation of arginine 65 to glycine abolished LD targeting. Increased levels of spastin-M1 expression reduced the number but increased the size of LDs. Expression of a mutant unable to bind and sever MTs caused clustering of LDs. Consistent with these findings, ubiquitous overexpression of Dspastin in Drosophila led to bigger and less numerous LDs in the fat bodies and increased triacylglycerol levels. In contrast, Dspastin overexpression increased LD number when expressed specifically in skeletal muscles or nerves. Downregulation of Dspastin and expression of a dominant-negative variant decreased LD numbers in Drosophila nerves, skeletal muscle and fat bodies, and reduced triacylglycerol levels in the larvae. Moreover, we found reduced amount of fat stores in intestinal cells of worms in which the spas-1 homologue was either depleted by RNA interference or deleted.

 

Taken together, our data uncovers an evolutionarily conserved role of spastin as a positive regulator of LD metabolism and open up the possibility that dysfunction of LDs in axons may contribute to the pathogenesis of HSP.

 

SOURCE: PLoS Genet. 2015 Apr 13;11(4):e1005149. doi: 10.1371/journal.pgen.1005149. eCollection 2015.

 

Spastin binds to lipid droplets and affects lipid metabolism.

 

Papadopoulos C1, Orso G2, Mancuso G1, Herholz M3, Gumeni S2, Tadepalle N1, Jüngst C4, Tzschichholz A5, Schauss A4, Höning S5, Trifunovic A3, Daga A2,Rugarli EI6.

 

1 Institute for Genetics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.

2 “E. MEDEA” Scientific Institute, Conegliano, Italy.

3 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne, Germany.

4 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.

5 Institute for Biochemistry I, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.

6 Institute for Genetics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.

 

 

Add your comment on this story