Abstract
Hereditary spastic paraplegias (HSPs) are genetically heterogeneous conditions caused by the progressive dying back of the longest axons in the central nervous system, the corticospinal axons. A wealth of data in the last decade has unraveled disturbances of lipid droplet (LD) biogenesis, maturation, turnover and contact sites in cellular and animal models with perturbed expression and function of HSP proteins. As ubiquitous organelles that segregate neutral lipid into a phospholipid monolayer, LDs are at the cross-road of several processes including lipid metabolism and trafficking, energy homeostasis, and stress signaling cascades. However, their role in brain cells, especially in neurons remains enigmatic. Here, we review experimental findings linking LD abnormalities to defective function of proteins encoded by HSP genes, and discuss arising questions in the context of the pathogenesis of HSP.
Highlights
Hereditary Spastic ParaplegiaIn humans, voluntary and fine motor movements are controlled by the corticospinal tract, which is composed of more than a million axons of the pyramidal motor neurons (Welniarz et al, 2017)
lipid droplet (LD) are assembled at the endoplasmic reticulum (ER) through a series of sequential steps beginning with fatty acids (FAs) activation by esterification with coenzyme A, followed by synthesis of TAG or sterol esters (SE) by enzymes residing in the ER
Seipin functions as gatekeeper at ER-LD contact sites to regulate LD formation with a mechanism that is not completely understood. Consistent with this role in LD biogenesis, human patients carrying loss-of-function mutations in BSCL2, the gene encoding for seipin, suffer from Berardinelli-Seip congenital lipodystrophy (Magre et al, 2001), a severe recessive disease characterized by abnormal fat deposition
Summary
Reviewed by: Giovanni Stevanin, INSERM U1127 Institut du Cerveau et de la Moelle épinière (ICM), France. Droplets in the Pathogenesis of Hereditary Spastic Paraplegia. Hereditary spastic paraplegias (HSPs) are genetically heterogeneous conditions caused by the progressive dying back of the longest axons in the central nervous system, the corticospinal axons. As ubiquitous organelles that segregate neutral lipid into a phospholipid monolayer, LDs are at the cross-road of several processes including lipid metabolism and trafficking, energy homeostasis, and stress signaling cascades. Their role in brain cells, especially in neurons remains enigmatic. We review experimental findings linking LD abnormalities to defective function of proteins encoded by HSP genes, and discuss arising questions in the context of the pathogenesis of HSP
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