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Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report.

ABSTRACT: Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) and curcumin administration on the course of the disease in a patient with adult TSD. The patient's serum cytokine profile was determined using multiplex analysis. The level of GM2 gangliosides in plasma was determined using mass spectrometry. The enzymatic activity of HexA in the plasma of the patient was assessed using a fluorescent substrate assay. The HexA α-subunit (HexA) concentration was determined using ELISA. It was shown that both UCBCT and curcumin administration led to a change in the patient's cytokine profile. The UCBCT resulted in an increase in the concentration of HexA in the patient's serum and in an improvement in the patient's neurological status. However, neither UCBCT nor curcumin were able to alter HexA activity and the level of GM2 in patient's plasma. The data obtained indicate that UCBCT and curcumin administration can alter the immunity of a patient with TSD, reduce the level of inflammatory cytokines and thereby improve the patient's condition.

SUBMITTER: Shaimardanova AA

PROVIDER: S-EPMC8539434 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report.

Shaimardanova Alisa A AA Chulpanova Daria S DS Solovyeva Valeriya V VV Garanina Ekaterina E EE Salafutdinov Ilnur I II Laikov Alexander Vladimirovich AV Kursenko Vadim V VV Chakrabarti Lisa L Zakharova Ekaterina Yu EY Bukina Tatiana M TM Baydakova Galina V GV Rizvanov Albert Anatolyevich AA

Life (Basel, Switzerland) 20210924 10

Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder that occurs due to a deficiency of a β hexosaminidase A (HexA) enzyme, resulting in the accumulation of GM2 gangliosides. In this work, we analyzed the effect of umbilical cord blood cell transplantation (UCBCT) and curcumin administration on the course of the disease in a patient with adult TSD. The patient's serum cytokine profile was determined using multiplex analysis. The level of GM2 gangliosides in p ...[more]

PMID: 34685379

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Project description:Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of β-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra bodies in both aged and ovalbumin-challenged adult PGRN-deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN-deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulins G and E domain and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD but may also have implications for developing PGRN-based therapy for this life-threatening disorder. KEY MESSAGES: GM2 accumulation and the existence of typical TSD cells containing zebra bodies are detected in both aged and ovalbumin-challenged adult PGRN deficient mice. Recombinant PGRN significantly reduces GM2 accumulation and lysosomal storage both in vivo and in vitro, which works through increasing the expression and lysosomal delivery of HexA. Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively binds to to HexA and reduces GM2 accumulation.

Project description:BackgroundTay-Sachs disease (TSD), a type of GM2-gangliosidosis, is a progressive neurodegenerative lysosomal storage disorder caused by mutations in the α subunit of the lysosomal β-hexosaminidase enzyme. This disease is characterized by excessive accumulation of GM2 ganglioside, predominantly in the central nervous system. Although Tay-Sachs patients appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to death. Recently, an early onset Tay-Sachs disease mouse model, with genotype Hexa-/-Neu3-/-, was generated. Progressive accumulation of GM2 led to premature death of the double KO mice. Importantly, this double-deficient mouse model displays typical features of Tay-Sachs patients, such as cytoplasmic vacuolization of nerve cells, deterioration of Purkinje cells, neuronal death, deceleration in movement, ataxia, and tremors. GM2-gangliosidosis is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage, and astrocyte activation, along with the production of inflammatory mediators. However, the mechanism of disease progression in Hexa-/-Neu3-/- mice, relevant to neuroinflammation is poorly understood.MethodIn this study, we investigated the onset and progression of neuroinflammatory changes in the cortex, cerebellum, and retina of Hexa-/-Neu3-/- mice and control littermates by using a combination of molecular genetics and immunochemical procedures.ResultsWe found elevated levels of pro-inflammatory cytokine and chemokine transcripts, such as Ccl2, Ccl3, Ccl4, and Cxcl10 and also extensive microglial and astrocyte activation and proliferation, accompanied by peripheral blood mononuclear cell infiltration in the vicinity of neurons and oligodendrocytes. Behavioral tests demonstrated a high level of anxiety, and age-dependent loss in both spatial learning and fear memory in Hexa-/-Neu3-/- mice compared with that in the controls.ConclusionAltogether, our data suggest that Hexa-/-Neu3-/- mice display a phenotype similar to Tay-Sachs patients suffering from chronic neuroinflammation triggered by GM2 accumulation. Furthermore, our work contributes to better understanding of the neuropathology in a mouse model of early onset Tay-Sachs disease.

Project description:GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in HEXA encoding the α-subunit and Sandhoff disease is caused by variants in HEXB encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable. We applied diffusion tensor imaging (DTI) and correlational fiber tractography to assess phenotypic differences in these two diseases. 40 DTI scans from 16 Late-Onset GM2 patients (NCT00029965) with either Sandhoff (n = 4), or Tay-Sachs (n = 12) disease. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and quantitative anisotropy (QA) were calculated in fiber tracts throughout the whole brain, arcuate fasciculus, corpus callosum, and cerebellum. Correlational tractography was also performed to identify fiber tracts with group wide differences in DTI metrics between Tay-Sachs and Sandhoff patients. A linear mixed effects model was used to analyze the differences between Tay-Sachs and Sandhoff patients. Tay-Sachs patients had higher MD in the left cerebellum (p = 0.003703), right cerebellum (p = 0.003435), superior cerebellar peduncle (SCP, p = 0.007332), and vermis (p = 0.01007). Sandhoff patients had higher FA in the left cerebellum (p = 0.005537), right cerebellum (p = 0.01905), SCP (p = 0.02844), and vermis (p = 0.02469). Correlational fiber tractography identified fiber tracts almost exclusively in cerebellar pathways with higher FA and QA, and lower MD, AD, and RD in Sandhoff patients compared to Tay-Sachs patients. Our study shows neurobiological differences between these two related disorders. To our knowledge, this is the first study using correlational tractography in a lysosomal storage disorder demonstrating these differences. This result indicates a greater burden of cerebellar pathology in Tay-Sachs patients compared with Sandoff patients.

Project description:GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), a substrate-specific cofactor for HexA. In their infantile, acute forms, these diseases rapidly progress with mental and psychomotor deterioration resulting in death by approximately 4 years of age. After gene transfer that overexpresses one of the deficient subunits, the amount of HexA heterodimer formed would empirically be limited by the availability of the other endogenous Hex subunit. The present study used a new variant of the human HexA α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM gene. Also, a previously published capsid mutant, AAV9.47, was used to deliver the gene to brain and spinal cord while having restricted biodistribution to the liver. The novel capsid and cassette design combination was characterized in vivo in TSD mice for its ability to efficiently transduce cells in the central nervous system when delivered intravenously in both adult and neonatal mice. This study demonstrates that the modified HexM is capable of degrading long-standing GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.

Dataset Information

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM2 Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report.

Publications

Serum Cytokine Profile, Beta-Hexosaminidase A Enzymatic Activity and GM<sub>2</sub> Ganglioside Levels in the Plasma of a Tay-Sachs Disease Patient after Cord Blood Cell Transplantation and Curcumin Administration: A Case Report.

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