Reductions of docosahexaenoic acid-containing phosphatidylcholine levels in the anterior horn of an ALS mouse model

Abstract

In this study, we analyzed the spatiotemporal alterations of phospholipid composition in the spinal cord of an amyotrophic lateral sclerosis (ALS) mouse model (G93A-mutated human superoxide dismutase 1 transgenic mice [SOD1(G93A) mice]) using imaging mass spectrometry (IMS), a powerful method to visualize spatial distributions of various types of molecules in situ. Using this technique, we deciphered the phospholipid distribution in the pre-symptomatic stage, early stage after disease onset, and terminal stages of disease in female SOD1(G93A) mouse spinal cords. These experiments revealed a significant decrease in levels of docosahexaenoic acid (DHA)-containing phosphatidylcholines (PCs), such as PC (diacyl-16:0/22:6), PC (diacyl-18:0/22:6), and PC (diacyl-18:1/22:6) in the L5 anterior horns of terminal stage (22-week-old) SOD1(G93A) mice. The reduction in PC (diacyl-16:0/22:6) level could be reflecting the loss of motor neurons themselves in the anterior horn of the spinal cord in ALS model mice. In contrast, other PCs, such as PC (diacyl-16:0/16:0), were observed specifically in the L5 dorsal horn gray matter, and their levels did not vary between ALS model mice and controls. Thus, our study showed a significant decrease in DHA-containing PCs, but not other PCs, in the terminal stage of ALS in model mice, which is likely to be a reflection of neuronal loss in the anterior horns of the spinal cords. Given its enrichment in dorsal sensory regions, the preservation of PC (diacyl-16:0/16:0) may be the result of spinal sensory neurons being unaffected in ALS. Taken together, these findings suggest that ALS spinal cords show significant alterations in PC metabolism only at the terminal stage of the disease, and that these changes are confined to specific anatomical regions and cell types.

Wildtype motoneurons, ALS‐Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling

“…We have compared metabolites altered in this in vitro ALS model to those found in the ALS mouse model (Patin et al, ) and in ALS patients (Blasco et al, ; Wuolikainen et al, ) (Table 4). We observed that in ALS‐associated condition, astrocytes displayed a low level of glycerophosphocholine as found in SOD1 G93A transgenic mice and additionally showed a decreased level of docosahexaenoic acid (DHA) as previously reported in SOD1 G93A mice (Arima et al, ). Phospholipids are used to synthesize sphingomyelins and are involved in the production of membranes (Moore et al, ).…”

TDP-43-Mediated Toxicity in HEK293T Cells: A Fast and Reproducible Protocol To Be Employed in the Search of New Therapeutic Options against Amyotrophic Lateral Sclerosis

“…Interestingly, we found a variety of glycerophospholipids decreased in this condition. Such a decrease was already shown in a SOD1-mouse model of ALS and could be related to the neuronal loss observed in these animals [36]. One possible hypothesis is that TDP-43 alters the composition of the cellular membrane and renders it more permeable (following the membrane hypothesis of aging [37]).…”

Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

“…The identification of the fatty acid chain 22:6 in the discriminant PCs of this model may correspond to the docosahexaenoic acid (DHA) involved in the maintenance of neuronal membranes, signal transduction, neuronal differentiation, neurogenesis, protection against synaptic loss, or spinal cord injury 21 . Whereas some authors have reported an association between the loss of motor neurons in the spinal cord in ALS model mice and the reduction in PC (diacyl-16:0/22:6) 22 , others have highlighted the significant increase of DHA in the frontal cortex of ALS patients 23 .…”