TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Abstract

Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.

ATP-binding cassette transporter expression is widely dysregulated in frontotemporal dementia with TDP-43 inclusions

“…Since neuroinflammation is widely considered as a hallmark of neurodegenerative diseases and its role in the aetiology of FTLD is of increasing interest ( Bright et al, 2019 ), the relationship between neuroinflammation, TARDBP and ABCA4 and ABCA13 should be further examined to determine if these ABCA transporters exhibit neuroprotective or more neurotoxic roles. Interestingly, there have been recent reports of TDP-43 inhibition of cholesterol biosynthesis through the master regulator of cholesterol homeostasis, sterol regulatory element-binding protein 2 ( Egawa et al, 2022 ), particularly in the ubiquitous oligodendrocytes harbouring TDP-3 inclusion pathology in FTLD-TDP ( Ho et al, 2021 ).…”

Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine

“…Downregulation of the cholesterol metabolism pathway has been reported in a meta-analysis of transcriptomics studies in SOD1-G93A mouse spinal cords [ 201 ]. Recently, two independent studies indicate that TDP-43, the key pathological hallmark protein for ALS [ 202 ], regulates SREBF2-mediated cholesterol metabolism [ 28 , 29 ]. Furthermore, the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme for cholesterol biosynthesis and a transcription target of SREBF2, is reduced in oligodendrocytes bearing TDP-43 pathologies [ 28 ], suggesting that cholesterol metabolism may be affected in cells with TDP-43 proteinopathies.…”

“…Furthermore, the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme for cholesterol biosynthesis and a transcription target of SREBF2, is reduced in oligodendrocytes bearing TDP-43 pathologies [ 28 ], suggesting that cholesterol metabolism may be affected in cells with TDP-43 proteinopathies. Although no change is observed in free cholesterol levels in the sera of ALS patients [ 29 ] as well as spinal cords of ALS patients and SOD1-G93A mice [ 35 ], the cholesterol level is reduced in the CSF of ALS patients [ 29 ]. Furthermore, reduced levels of lanosterol, a precursor to cholesterol, are observed in ALS patients and SOD1 mouse models, along with downregulation of HMGCR [ 35 ].…”

“…Evidence of TDP-43-mediated cholesterol dysregulations has been found in oligodendrocytes harboring TDP-43 pathologies [ 28 ]. Furthermore, CSF cholesterol level is reduced in ALS patients [ 29 ]. These studies together suggest complex cell–cell communication and transport, and perhaps a cell-type specific mechanism of lipid-mediated toxicity in ALS.…”

“…Patients with elevated serum levels of triglycerides (TGs) [ 22 ] and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio [ 21 ] have extended survival by nearly a year. In addition, we and others have also shown that TDP-43, the pathological hallmark and one of the causal genes for ALS, regulates sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol metabolism [ 28 , 29 ]. Taken together, these observations indicate that lipid dysmetabolism is an integral part of ALS pathogenesis, and thus, lipids could serve as biomarkers and therapeutic targets.…”