Lipids in the Physiopathology of Hereditary Spastic Paraplegias

Abstract

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.

Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

“…Disrupted ER, on which LDs form, and decreased Drp1 levels may therefore synergistically contribute to neurodegeneration in our model of HSP by disrupting LD formation. Interestingly, defects in lipid metabolism and storage within LDs are increasingly being associated with HSPs suggesting that lipid biogenesis may contribute to the pathophysiology of these diseases [64].…”

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

“…The extreme polarization of cortical motor neurons makes them vulnerable to even minor disturbances of a plethora of pathways. Disruption or abnormalities of endosomal trafficking and dynamics, mitochondrial quality control, endoplasmic reticulum (ER) morphogenesis, cargo-mediated transport on the microtubules, lysosomal function, and lipid metabolism play a role in the pathogenesis of HSP ( Blackstone et al, 2011 ; Rugarli and Langer, 2012 ; Allison et al, 2017 ; Blackstone, 2018a ; Darios et al, 2020 ). Here, we focus on the intriguing connection between several HSP proteins and the biology of lipid droplets, and discuss the possible role of LD dysfunction in the pathogenesis of the disease.…”

Hereditary Spastic Paraplegia and Future Therapeutic Directions: Beneficial Effects of Small Compounds Acting on Cellular Stress

“…Although little is known about the mechanisms related to neurodegeneration in complicated forms, the functional studies carried out in recent years on HSP-linked genes have suggested that alterations of intracellular trafficking may be a common element. The affected cellular functions include lipid metabolism, active axonal transport, organelle shaping, and the endo-lysosomal system ( Boutry et al, 2019a ; Darios et al, 2020 ; Öztürk et al, 2020 ). Although the progress made in deciphering the pathological process underlying HSP, there is still no specific cure to prevent or slow down neuronal degeneration or dysfunction.…”