Substrate reduction therapy using Genz‐667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease

Blumenreich, Shani; Yaacobi, Chen; Vardi, Ayelet; Barav, Or B.; Vitner, Einat B.; Park, Hye-Jung; Wang, Bing; Cheng, Seng H.; Sardi, S. Pablo; Futerman, Anthony H.

doi:10.1111/jnc.15136

Cited by 22 publications

(24 citation statements)

References 33 publications

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“…APOD and APOE, are involved in the removal of lipids during nerve cell degeneration [62], which may be of importance in demyelination. Moreover, levels of two PLIN proteins (PLIN 3 and 4) were elevated in the MLIV brain and in neuronal forms of Gaucher disease [63,64]. Lipid droplets have been implicated in neurodegeneration [65,66] including in Parkinson's disease, which suggest that they play a broad role in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

Vardi

Pri-Or

Wigoda

et al. 2021

Orphanet J Rare Dis

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Background Mucolipidosis type IV (MLIV), an ultra-rare neurodevelopmental and neurodegenerative disorder, is caused by mutations in the MCOLN1 gene, which encodes the late endosomal/lysosomal transient receptor potential channel TRPML1 (mucolipin 1). The precise pathophysiogical pathways that cause neurological disease in MLIV are poorly understood. Recently, the first post-mortem brain sample became available from a single MLIV patient, and in the current study we performed mass spectrometry (MS)-based proteomics on this tissue with a view to delineating pathological pathways, and to compare with previously-published data on MLIV, including studies using the Mcoln1−/− mouse. Results A number of pathways were altered in two brain regions from the MLIV patient, including those related to the lysosome, lipid metabolism, myelination, cellular trafficking and autophagy, mTOR and calmodulin, the complement system and interferon signaling. Of these, levels of some proteins not known previously to be associated with MLIV were altered, including APOD, PLIN4, ATG and proteins related to interferon signaling. Moreover, when proteins detected by proteomics in the human brain were compared with their orthologs detected in the Mcoln1−/− mouse by RNAseq, the results were remarkably similar. Finally, analysis of proteins in human and mouse CSF suggest that calbindin 1 and calbindin 2 might be useful as biomarkers to help chart the course of disease development. Conclusions Despite the sample size limitations, our findings are consistent with the relatively general changes in lysosomal function previously reported in MLIV, and shed light on new pathways of disease pathophysiology, which is required in order to understand the course of disease development and to determine the efficacy of therapies when they become available for this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

Vardi

Pri-Or

Wigoda

et al. 2021

Orphanet J Rare Dis

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“…A Phase III clinical trial of venglustat showed promise in improving biochemical and phenotypic parameters in GD3 patients [ 21 ]. An analogue of venglustat, GZ-682452 (termed herein as GZ452), was effective at attenuating several neuropathologic and behavioral manifestations associated with nGD mouse models [ 22 , 23 , 24 ]. However, the underlying mechanism(s) of SRT in protecting cellular functions are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease

Peng

Liou

Lin

et al. 2021

Cells

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Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

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“…2 A). Tg2576 mice were fed either a control diet or a GCSi formulated diet, which we previously reported lowers glycosphingolipid levels and reduces neuropathological features of disease in mouse models of Gaucher disease [ 5 ], Parkinson disease [ 44 ], and amyotrophic lateral sclerosis [ 16 ]. In WT mice, regional variations in total GlcCer and GM3 levels were observed in the cortex, hippocampus, and amygdala (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Animals were housed under light: dark (12:12 h) cycles and provided with food and water ad libitum. In all GCSi treatment studies, compound (GENZ-667161) was administered at 60 mg/kg/day in formulated diet as previously described [ 5 , 16 , 31 , 44 ]. All procedures were performed using protocols approved by Sanofi Genzyme’s Institutional Animal Care and Use Committees.…”

Section: Methodsmentioning

confidence: 99%

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Glucosylceramide synthase inhibition reduces ganglioside GM3 accumulation, alleviates amyloid neuropathology, and stabilizes remote contextual memory in a mouse model of Alzheimer’s disease

et al. 2022

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Background Gangliosides are highly enriched in the brain and are critical for its normal development and function. However, in some rare neurometabolic diseases, a deficiency in lysosomal ganglioside hydrolysis is pathogenic and leads to early-onset neurodegeneration, neuroinflammation, demyelination, and dementia. Increasing evidence also suggests that more subtle ganglioside accumulation contributes to the pathogenesis of more common neurological disorders including Alzheimer’s disease (AD). Notably, ganglioside GM3 levels are elevated in the brains of AD patients and in several mouse models of AD, and plasma GM3 levels positively correlate with disease severity in AD patients. Methods Tg2576 AD model mice were fed chow formulated with a small molecule inhibitor of glucosylceramide synthase (GCSi) to determine whether reducing glycosphingolipid synthesis affected aberrant GM3 accumulation, amyloid burden, and disease manifestations in cognitive impairment. GM3 was measured with LC-MS, amyloid burden with ELISA and amyloid red staining, and memory was assessed using the contextual fear chamber test. Results GCSi mitigated soluble Aβ42 accumulation in the brains of AD model mice when treatment was started prophylactically. Remarkably, GCSi treatment also reduced soluble Aβ42 levels and amyloid plaque burden in aged (i.e., 70 weeks old) AD mice with preexisting neuropathology. Our analysis of contextual memory in Tg2576 mice showed that impairments in remote (cortical-dependent) memory consolidation preceded deficits in short-term (hippocampal-dependent) contextual memory, which was consistent with soluble Aβ42 accumulation occurring more rapidly in the cortex of AD mice compared to the hippocampus. Notably, GCSi treatment significantly stabilized remote memory consolidation in AD mice—especially in mice with enhanced cognitive training. This finding was consistent with GCSi treatment lowering aberrant GM3 accumulation in the cortex of AD mice. Conclusions Collectively, our results indicate that glycosphingolipids regulated by GCS are important modulators of Aβ neuropathology and that glycosphingolipid homeostasis plays a critical role in the consolidation of remote memories.

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Substrate reduction therapy using Genz‐667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease

Cited by 22 publications

References 33 publications

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

Proteomics analysis of a human brain sample from a mucolipidosis type IV patient reveals pathophysiological pathways

Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease

Glucosylceramide synthase inhibition reduces ganglioside GM3 accumulation, alleviates amyloid neuropathology, and stabilizes remote contextual memory in a mouse model of Alzheimer’s disease

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