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

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.

Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis

“…Interestingly, the authors reported a larger survival extension in males (76% in males, 24% in females) (Rossaert et al, 2019). The beneficial effect of the molecule was associated with a mitigation of lipid metabolism alterations and a restoration of global histone acetylation, but not with a reduction of astrocytosis nor microgliosis (Rossaert et al, 2019;Burg et al, 2021).…”

Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine

“…PC is a main source of acetylcholine in the CNS, and intake of PC can improve memory and learning and ameliorate cognitive decline in mouse models of dementia [118][119][120]. Elevated levels of PC have been reported in the CSF [65] and the spinal cord nuclear lipidome [70] of ALS patients, the spinal cords of FUS overexpression mice [68], the skeletal muscle of SOD1-G86R mice [67], and the motor cortex of SOD1-G93A mice [69]. Elevated levels of PC 44:8 and PC 36:4 have been found to be the most discriminatory in the CSF and plasma, being able to differentiate between slow-and fast-progression cases [61,65].…”

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

“…metabolism [24], dysfunctions of T-regulatory (Tregs) lymphocytes [25], and defects in protein and RNA degradation and homeostasis [26] seem to act as major contributors to the progression of the disease. Most of the patients affected by ALS are characterized by an unknown etiology.…”

“…Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the selective degeneration of motor neurons in the spinal cord, motor cortex, and brainstem [ 23 ]. The etiology of this pathology is still not well known; defects in the metabolism [ 24 ], dysfunctions of T-regulatory (Tregs) lymphocytes [ 25 ], and defects in protein and RNA degradation and homeostasis [ 26 ] seem to act as major contributors to the progression of the disease. Most of the patients affected by ALS are characterized by an unknown etiology.…”