Nuclear lipidome is altered in amyotrophic lateral sclerosis: A pilot study

Abstract

Nucleocytosolic transport, a membrane process, is impaired in motor neurons in amyotrophic lateral sclerosis (ALS). This study analyzes the nuclear lipidome in motor neurons in ALS and examines molecular pathways linked to the major lipid alterations. Nuclei were obtained from the frozen anterior horn of the lumbar spinal cord of ALS patients and age-matched controls. Lipidomic profiles of this subcellular fraction were obtained using liquid chromatography and mass spectrometry. We validated the mechanisms behind presumable lipidomic changes by exploring ALS surrogate models including human motor neurons (derived from ALS lines and controls) subjected to oxidative stress, the hSOD-G93A transgenic mice, and samples from an independent cohort of ALS patients. Among the differential lipid species, we noted 41 potential identities, mostly belonging to phospholipids (particularly ether phospholipids, as plasmalogens), as well as diacylglycerols and triacylglycerides. Decreased expression of alkyldihydroxyacetonephosphate synthase (AGPS)-a critical peroxisomal enzyme in plasmalogen synthesis-is found in motor neuron disease models; this occurs in parallel with an increase in the expression of sterol carrier protein 2 (SCP2) mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified diminished expression of diacylglycerol-related enzymes, such as phospholipase C βI | 483 RAMÍREZ-NUÑEZ Et Al.

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Previous lipidomic studies in the spinal cord of SOD1 models have pointed to specific alterations in neurons and astrocytes. Analysis of the nuclear lipidome of SOD1 motor neurons showed defects mostly in glycerophospholipids, diacylglycerol, and triacylglycerides [ 59 ], whereas a bulk lipidomic analysis suggested the accumulation of CE in astrocytes lipid droplets [ 28 ]. Although, accumulation of lipid droplets has also been observed in motor neurons and more recently in microglia of aged brains [ 59 , 60 ].…”

“…Analysis of the nuclear lipidome of SOD1 motor neurons showed defects mostly in glycerophospholipids, diacylglycerol, and triacylglycerides [ 59 ], whereas a bulk lipidomic analysis suggested the accumulation of CE in astrocytes lipid droplets [ 28 ]. Although, accumulation of lipid droplets has also been observed in motor neurons and more recently in microglia of aged brains [ 59 , 60 ]. Intriguingly, the role of microglia in lipid homeostasis has never been explored in ALS.…”

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

“…TDP-43 is also linked to the cytoplasmic accumulation of other nuclear membrane proteins, like Nup62 and Kpnb1 [13]. Of note, we have recently demonstrated that ALS is associated with an alteration in the nuclear envelope lipids [14].…”

“…All these factors require nucleocytosolic transport; therefore, a loss in this cellular property's homeostasis may partially explain their presence in the cytosol. Indeed, we have recently reported that the nuclear envelope (where the proteins responsible for nucleocytoplasmic shuttling reside) showed altered properties in ALS patients and models [14].…”

Cell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichment

“…TDP-43 is also linked to the cytoplasmic accumulation of other nuclear membrane proteins like Nup62 and Kpnb1 [13]. Of note, we have recently demonstrated that ALS is associated with an alteration in the nuclear envelope lipids [14] Besides p-TDP-43, p-ERK [7] and REST [10] also show aggregates in neurodegenerative diseases. Several authors have reported that TDP-43 protein aggregates may be found in organullar fractions in addition to the cytosolic location, such as mitochondria [15,16].…”