DDHD1 and DDHD2 HSP genes investigated

Posted - February 2018 in Research Highlights

Lipid metabolism dysfunction the common cause

 

Here are reports on two studies.

 

SPG54 HSP mice were used to study how lipid droplets accumulate in the neurons, causing this form of HSP associated with mutations in the DDHD2 gene.

 

Abstract

Deleterious mutations in the serine lipase DDHD2 are a causative basis of complex hereditary spastic paraplegia (HSP, subtype SPG54) in humans. We recently found that DDHD2 is a principal triglyceride hydrolase in the central nervous system (CNS) and that genetic deletion of this enzyme in mice leads to ectopic lipid droplet (LD) accumulation in neurons throughout the brain. Nonetheless, how HSP-related mutations in DDHD2 relate to triglyceride metabolism and LD formation remains poorly understood.

 

Here, we have characterized a set of HSP-related mutations in DDHD2 and found that they disrupt triglyceride hydrolase activity in vitro and impair the capacity of DDHD2 to protect cells from LD accumulation following exposure to free fatty acid, an outcome that was also observed with a DDHD2-selective inhibitor.

 

We furthermore isolated and characterized LDs from brain tissue of DDHD2-/- mice, revealing that they contain both established LD-associated proteins identified previously in other organs and CNS-enriched proteins, including several proteins with genetic links to human neurological disease.

 

These data, taken together, indicate that the genetic inactivation of DDHD2, as caused by HSP-associated mutations, substantially perturbs lipid homeostasis and the formation and content of LDs, underscoring the importance of triglyceride metabolism for normal CNS function and the key role that DDHD2 plays in this process.

 

SOURCE: Biochemistry. 2018 Feb 6;57(5):827-838. doi: 10.1021/acs.biochem.7b01028. Epub 2017 Dec 26. PMID: 29278326

 

Functional Contribution of the Spastic Paraplegia-Related Triglyceride Hydrolase DDHD2 to the Formation and Content of Lipid Droplets.

 

Inloes JM1, Kiosses WB2, Wang H3,4,5,6, Walther TC5,6,7,8, Farese RV Jr.5,6,7, Cravatt BF1.

1 Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037, United States.

2 Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037, United States.

3 University Libraries, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States.

4 Department of Biological Sciences, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States.

5 Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health , Boston, Massachusetts 02115, United States.

6 Department of Cell Biology, Harvard Medical School , Boston, Massachusetts 02115, United States.

7 Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.

8 Howard Hughes Medical Institute , Boston, Massachusetts 02115, United States.

 


 

SPG28 HSP is now associated with complex as well as pure HSP. A new mutation in the DDHD1 gene associated with this complex form of SPG28 HSP was discovered, with features of accumulation in the brain and retinal  problems due to abnormal lipid function in the eye.

 

Abstract

Defects of phospholipids remodelling and synthesis are inborn errors of metabolism responsible for various clinical presentations including spastic paraplegia, retinopathy, optic atrophy, myo- and cardiomyopathies, and osteo-cutaneous manifestations. DDHD1 encodes a phospholipase A1, which is involved in the remodelling of phospholipids. We previously described a relatively pure hereditary spastic paraplegia (HSP) phenotype associated with mutations in DDHD1.

 

Here we report a complex form of HSP associated with retinal dystrophy and a pattern of neurodegeneration with brain iron accumulation (NBIA) on brain MRI, due to a novel homozygous mutation in DDHD1. This observation enlarges the clinical spectrum of DDHD1-associated disorders and sheds light on a new aetiology for syndromes associating retinopathy and NBIA. It also emphasizes the role of complex lipids in the retina.

 

SOURCE: Eur J Med Genet. 2017 Dec;60(12):639-642. doi: 10.1016/j.ejmg.2017.08.015. Epub 2017 Aug 14. PMID: 28818478

 

Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation.

 

Dard R1, Meyniel C2, Touitou V3, Stevanin G4, Lamari F5, Durr A6, Ewenczyk C6, Mochel F7.

1 AP-HP, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; CHI Poissy St Germain-en-Laye, Département de Génétique, Cytogénétique et Biologie de la Reproduction, St Germain-en-Laye, France.

2 AP-HP, Département de Neurophysiologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

3 AP-HP, Département d’Ophtalmologie, DHU Vision et Handicaps, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

4 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

5 AP-HP, Laboratoire de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Université Pierre et Marie Curie, Groupe de Recherche Clinique Neurométabolique, Paris, France.

6 AP-HP, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

7 AP-HP, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Université Pierre et Marie Curie, Groupe de Recherche Clinique Neurométabolique, Paris, France. Electronic address: [email protected]

Add your comment on this story