SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment

Stoffel, Wilhelm; Jenke, Britta; Schmidt‐Soltau, Inga; Binczek, Erika; Brodesser, Susanne; Hammels, Ina

doi:10.1038/s41419-018-0560-7

Cited by 21 publications

(15 citation statements)

References 63 publications

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“…Given that nSMase2 inactivation triggers neurotoxicity with TDP-43 aggregation via impaired exosome formation, and TDP-43 pathology is a characteristic hallmark of motor neuron degeneration in SCA2, this dysregulation appears to be a pathogenic event [28,33,117]. In addition, nSMase2 deficiency triggers tauopathy, and ataxin-2 deficiency has a specific rescue effect not only for TDP-43 neurotoxicity but also in general on tauopathies [29,118], so the chronic transcriptional downregulation of Smpd3 might be a contributor to the SCA2-specific process of neurodegeneration. The transcript Smpd4 coding for nSMase3 in the ER and the Golgi apparatus was found unchanged, while Smpd5 coding for mitochondrial nSMase (MA-nSMase) was found upregulated in both tissues, reaching significance in cerebellum (cerebellum: 135%, p = 0.0454; spinal cord: 153%, p = 0.0940).…”

Section: Resultsmentioning

confidence: 99%

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen

Arsovic

Meierhofer

et al. 2019

IJMS

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Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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Section: Resultsmentioning

confidence: 99%

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen

Arsovic

Meierhofer

et al. 2019

IJMS

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“…These results reveal the importance of the Golgi in AD (Joshi et al, 2014). In addition, Stoffel et al (2018) found that neutral sphingomyelinase, smpd3, expression in the central nervous system is restricted to the GA of neurons. In the brains of smpd3−/− mice, Golgi vesicular protein transport in neurons is inhibited, which leads to Aβ deposition, UPR, and apoptosis.…”

Section: Alzheimer's Diseasementioning

confidence: 60%

“…In the brains of smpd3−/− mice, Golgi vesicular protein transport in neurons is inhibited, which leads to Aβ deposition, UPR, and apoptosis. Finally, smpd3−/− mice show a progressive cognitive decline similar to the clinical manifestations of familial and sporadic AD, indicating that smpd3 may be a susceptible gene for AD (Stoffel et al, 2018).…”

Section: Alzheimer's Diseasementioning

confidence: 92%

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases

Liu

Deng

et al. 2020

Front. Cell Dev. Biol.

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Increasing evidence shows that, in addition to the classical function of protein processing and transport, the Golgi apparatus (GA) is also involved in apoptosis, one of the most common forms of cell death. The structure and the function of the GA is damaged during apoptosis. However, the specific effect of the GA on the apoptosis process is unclear; it may be involved in initiating or promoting apoptosis, or it may inhibit apoptosis. Golgi-related apoptosis is associated with a variety of neurological diseases including glioma, Alzheimer's disease (AD), Parkinson's disease (PD), and ischemic stroke. This review summarizes the changes and the possible mechanisms of Golgi structure and function during apoptosis. In addition, we also explore the possible mechanisms by which the GA regulates apoptosis and summarize the potential relationship between the Golgi and certain neurological diseases from the perspective of apoptosis. Elucidation of the interaction between the GA and apoptosis broadens our understanding of the pathological mechanisms of neurological diseases and provides new research directions for the treatment of these diseases. Therefore, we propose that the GA may be a potential therapeutic target for apoptosis-related neurological diseases.

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“…Similarly, a deficiency of Smpd3 encoding nSMase2 as detected in the KIN nervous tissue was reported to cause TDP-43 neurotoxicity and tauopathy, while Ataxin-2 depletion protects against TDP-43 aggregation and tauopathies, so this dysregulation appears to be another pathogenic event with SCA2-typical features. It appears most promising as a molecular biomarker for neuroprotective treatments in SCA2 and ALS [28,29,33,112,113]. In comparison, the subtle deficiency of Sptlc2 mRNA in the KIN mouse is associated with the peripheral neuropathy in HSAN1, and the marked deficit of aSMase protein in the KIN mouse is associated with the neuronopathic NPC discorder, so both events in SCA2 may contribute to pathogenesis, but they mediate two relatively unspecific clinical aspects.…”

Section: Discussionmentioning

confidence: 99%

“…Given that nSMase2 inactivation triggers neurotoxicity with TDP-43 aggregation via impaired exosome formation, and TDP-43 pathology is a characteristic hallmark of motor neuron degeneration in SCA2, this dysregulation appears to be a pathogenic event [28,33,112]. In addition, nSMase2 deficiency triggers tauopathy, and Ataxin-2 deficiency has a specific rescue effect not only for TDP-43 neurotoxicity, but also in general on tauopathies [29,113], so the chronic transcriptional downregulation of Smpd3 might be a contributor to the SCA2-specific process of neurodegeneration. Smpd4 encoding for nSMase3 in ER and Golgi apparatus was found unchanged, while Smpd5 encoding for mitochondrial nSMase (MA-nSMase) was found upregulated in both tissues, reaching significance in cerebellum (cerebellum: 135%, p = 0.0454; spinal cord: 153%, p = 0.0940).…”

Section: Enzymatic Production Of Ceramide In Atxn2-cag100-kin Mouse Nmentioning

confidence: 99%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

show abstract

SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment

Cited by 21 publications

References 63 publications

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

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