Fundamental processes and potential drug targets
As lipids are a major constituent of cell membranes, alterations in their metabolism is likely to alter membrane-related functions, which in turn impacts cellular functions and could contribute to neurodegeneration. HSP gene mutations can also impact lipid metabolism secondarily rather than directly.
Here are 3 new published papers on the topic.
Alteration of synthesis, metabolism, degradation and trafficking across multiple classes of cell lipids are explored in depth in this review.
The review also examines dysfunction in mitochondria and lysosomes, and the importance of myelin for axon maintenance.
Despite all that is known, the link between lipid metabolism and neurodegeneration is still unclear in most forms of HSP. Studies that modulate lipid metabolism are required to evaluate the role of lipids in neurodegeneration. Theoretically, lipid metabolism can respond to drug treatment, so greater understanding could help to identify therapeutic targets for drugs.
Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases sharing spasticity in lower limbs as common symptom. There is a large clinical variability in the presentation of patients, partly underlined by the large genetic heterogeneity, with more than 60 genes responsible for HSP. Despite this large heterogeneity, the proteins with known function are supposed to be involved in a limited number of cellular compartments such as shaping of the endoplasmic reticulum or endolysosomal function. Yet, it is difficult to understand why alteration of such different cellular compartments can lead to degeneration of the axons of cortical motor neurons.
A common feature that has emerged over the last decade is the alteration of lipid metabolism in this group of pathologies. This was first revealed by the identification of mutations in genes encoding proteins that have or are supposed to have enzymatic activities on lipid substrates. However, it also appears that mutations in genes affecting endoplasmic reticulum, mitochondria, or endolysosome function can lead to changes in lipid distribution or metabolism.
The aim of this review is to discuss the role of lipid metabolism alterations in the physiopathology of HSP, to evaluate how such alterations contribute to neurodegenerative phenotypes, and to understand how this knowledge can help develop therapeutic strategy for HSP.
SOURCE: Front Neurosci. 2020 Feb 28;14:74. doi: 10.3389/fnins.2020.00074. eCollection 2020. Copyright © 2020 Darios, Mochel and Stevanin. PMID: 32180696
Lipids in the Physiopathology of Hereditary Spastic Paraplegias
1 Sorbonne Université, Paris, France.
2 Inserm, U1127, Paris, France.
3 CNRS, UMR 7225, Paris, France.
4 Institut du Cerveau et de la Moelle Epinière, Paris, France.
5 National Reference Center for Neurometabolic Diseases, Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
6 Equipe de Neurogénétique, Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France.
Spastin regulates lipid droplets in cells
Role in shaping endoplasmic reticulum as well
Tightly controlled levels of the M1 isoform of Spastin are necessary for healthy cells. Spastin has a dual role in shaping endoplasmic reticulum (ER) tubules and regulating lipid droplet (LD) movement along microtubules (MT).
Lipid droplets (LDs) are metabolic organelles that store neutral lipids and dynamically respond to changes in energy availability by accumulating or mobilizing triacylglycerols (TAGs). How the plastic behavior of LDs is regulated is poorly understood.
Hereditary spastic paraplegia is a central motor axonopathy predominantly caused by mutations in SPAST, encoding the microtubule-severing protein spastin. The spastin-M1 isoform localizes to nascent LDs in mammalian cells; however, the mechanistic significance of this targeting is not fully explained.
Here, we show that tightly controlled levels of spastin-M1 are required to inhibit LD biogenesis and TAG accumulation. Spastin-M1 maintains the morphogenesis of the ER when TAG synthesis is prevented, independent from microtubule binding. Moreover, spastin plays a microtubule-dependent role in mediating the dispersion of LDs from the ER upon glucose starvation.
Our results reveal a dual role of spastin to shape ER tubules and to regulate LD movement along microtubules, opening new perspectives for the pathogenesis of hereditary spastic paraplegia.
SOURCE: Life Sci Alliance. 2020 Apr 22;3(6):e202000715. doi: 10.26508/lsa.202000715. Print 2020 Jun. © 2020 Tadepalle et al. PMID: 32321733
Microtubule-dependent and independent roles of spastin in lipid droplet dispersion and biogenesis
1 Institute for Genetics, University of Cologne, Cologne, Germany
2 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
3 Institute for Biochemistry I, University of Cologne, Cologne, Germany
Spastin controls lipid droplet dispersion
Disruption leads to clinical features of SPG4
In non-HSP neurons, the M1 isoform of Spastin controls lipid droplet (LD) dispersion by influencing the shape of the endoplasmic reticulum (ER) along microtubules (MT). In neurons with a harmful mutation in SPAST, Spastin protein depletion disrupts this mechanism and impacts the LD network, leading to the clinical features of SPG4.
Lipid droplets (LD) are affected in multiple human disorders. These highly dynamic organelles are involved in many cellular roles. While their intracellular dispersion is crucial to ensure their function and other organelles-contact, underlying mechanisms are still unclear.
Here we show that Spastin, one of the major proteins involved in Hereditary Spastic Paraplegia (HSP), controls LD dispersion. Spastin depletion in zebrafish affects metabolic properties and organelle dynamics. These functions are ensured by a conserved complex set of splice variants. M1 isoforms determine LD dispersion in the cell by orchestrating endoplasmic reticulum (ER) shape along microtubules (MTs). To further impact LD fate, Spastin modulates transcripts levels and subcellular location of other HSP key players, notably Seipin and REEP1.
In pathological conditions, mutations in human Spastin M1 disrupt this mechanism and impacts LD network. Spastin depletion influences not only other key proteins but also modulates specific neutral lipids and phospholipids, revealing an impact on membrane and organelle components. Altogether our results show that Spastin and its partners converge in a common machinery that coordinates LD dispersion and ER shape along MTs. Any alteration of this system results in HSP clinical features and impacts lipids profile, thus opening new avenues for novel biomarkers of HSP.
SOURCE: PLoS Genet. 2020 Apr 21;16(4):e1008665. doi: 10.1371/journal.pgen.1008665. eCollection 2020 Apr. PMID: 32315314
Spastin mutations impair coordination between lipid droplet dispersion and reticulum
1 Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, School of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
2 Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
3 Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland