Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside

María José Virgolini, Constanza Feliziani, María Julia Cambiasso, Pablo Lopez, Mariana Bollo

Research output: Contribution to journalArticle

Abstract

GM2-gangliosidosis, a subgroup of lysosomal storage disorders, is caused by deficiency of hexosaminidase activity, and comprises the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents normal metabolization of ganglioside GM2, usually resulting in progressive neurodegenerative disease. The molecular mechanisms whereby GM2 accumulation in neurons triggers neurodegeneration remain unclear. In vitro experiments, using microsomes from Sandhoff mouse model brain, showed that increase of GM2 content negatively modulates sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) (Pelled et al., 2003). Furthermore, Ca2+ depletion in endoplasmic reticulum (ER) triggers Unfolded Protein Response (UPR), which tends to restore homeostasis in the ER; however, if cellular damage persists, an apoptotic response is initiated. We found that ER GM2 accumulation in cultured neurons induces luminal Ca2+ depletion, which in turn activates PERK (protein kinase RNA [PKR]-like ER kinase), one of three UPR sensors. PERK signaling displayed biphasic activation; i.e., early upregulation of cytoprotective calcineurin (CN) and, under prolonged ER stress, enhanced expression of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Moreover, GM2 accumulation in neuronal cells induced neurite atrophy and apoptosis. Both processes were effectively modulated by treatment with the selective PERK inhibitor GSK2606414, by CN knockdown, and by CHOP knockdown. Overall, our findings demonstrate the essential role of PERK signaling pathway contributing to neurodegeneration in a model of GM2-gangliosidosis.

Original languageEnglish (US)
Pages (from-to)225-239
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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G(M2) Ganglioside
Neurites
Endoplasmic Reticulum
Atrophy
GM2 Gangliosidosis
Transcription Factor CHOP
Apoptosis
Unfolded Protein Response
Sandhoff Disease
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Tay-Sachs Disease
Neurons
Hexosaminidases
Endoplasmic Reticulum Stress
Calcineurin
Microsomes
Neurodegenerative Diseases
Protein Kinases
Homeostasis
Transcription Factors

Keywords

  • Calcium
  • GM2 ganglioside
  • Neurodegeneration
  • Protein kinase RNA [PKR]-like ER kinase (PERK)
  • Transcription factor C/EBP homologous protein (CHOP)
  • Unfolded Protein Response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. / Virgolini, María José; Feliziani, Constanza; Cambiasso, María Julia; Lopez, Pablo; Bollo, Mariana.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1866, No. 2, 01.02.2019, p. 225-239.

Research output: Contribution to journalArticle

Virgolini, María José ; Feliziani, Constanza ; Cambiasso, María Julia ; Lopez, Pablo ; Bollo, Mariana. / Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2019 ; Vol. 1866, No. 2. pp. 225-239.
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