Dataset Information

Autophagy Signaling by Neural-Induced Human Adipose Tissue-Derived Stem Cell-Conditioned Medium during Rotenone-Induced Toxicity in SH-SY5Y Cells.

ABSTRACT: Rotenone (ROT) inhibits mitochondrial complex I, leading to reactive oxygen species formation, which causes neurodegeneration and alpha-synuclein (α-syn) aggregation and, consequently, Parkinson's disease. We previously found that a neurogenic differentiated human adipose tissue-derived stem cell-conditioned medium (NI-hADSC-CM) was protective against ROT-induced toxicity in SH-SY5Y cells. In the present study, ROT significantly decreased the phospho (p)-mTORC1/total (t)-mTOR, p-mTORC2/t-mTOR, and p-/t-ULK1 ratios and the ATG13 level by increasing the DEPTOR level and p-/t-AMPK ratio. Moreover, ROT increased the p-/t-Akt ratio and glycogen synthase kinase-3β (GSK3β) activity by decreasing the p-/t-ERK1/2 ratios and beclin-1 level. ROT also promoted the lipidation of LC3B-I to LC3B-II by inducing autophagosome formation in Triton X-100-soluble and -insoluble cell lysate fractions. Additionally, the levels of ATG3, 5, 7, and 12 were decreased, along with those of lysosomal LAMP1, LAMP2, and TFEB, leading to lysosomal dysfunction. However, NI-hADSC-CM treatment increased the p-mTORC1, p-mTORC2, p-ULK1, p-Akt, p-ERK1/2, ATG13, and beclin-1 levels and decreased the p-AMPK level and GSK3β activity in response to ROT-induced toxicity. Additionally, NI-hADSC-CM restored the LC3B-I level, increased the p62 level, and normalized the ATG and lysosomal protein amounts to control levels. Autophagy array revealed that the secreted proteins in NI-hADSC-CM could be crucial in the neuroprotection. Taken together, our results showed that the neuroprotective effects of NI-hADSC-CM on the autophagy signaling pathways could alleviate the aggregation of α-syn in Parkinson's disease and other neurodegenerative disorders.

SUBMITTER: Ramalingam M

PROVIDER: S-EPMC9031864 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Autophagy Signaling by Neural-Induced Human Adipose Tissue-Derived Stem Cell-Conditioned Medium during Rotenone-Induced Toxicity in SH-SY5Y Cells.

Ramalingam Mahesh M Jeong Han-Seong HS Hwang Jinsu J Cho Hyong-Ho HH Kim Byeong C BC Kim Eungpil E Jang Sujeong S

International journal of molecular sciences 20220410 8

Rotenone (ROT) inhibits mitochondrial complex I, leading to reactive oxygen species formation, which causes neurodegeneration and alpha-synuclein (α-syn) aggregation and, consequently, Parkinson's disease. We previously found that a neurogenic differentiated human adipose tissue-derived stem cell-conditioned medium (NI-hADSC-CM) was protective against ROT-induced toxicity in SH-SY5Y cells. In the present study, ROT significantly decreased the phospho (p)-mTORC1/total (t)-mTOR, p-mTORC2/t-mTOR, a ...[more]

PMID: 35457010

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Project description:Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. To unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes, respectively, and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP(+) and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP(+) and rotenone dose-dependently elevated the levels of intracellular free Ca(2+) and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP(+) and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators cyclooxygenase-2 (Cox-2 and cleaved p10 fragment of caspase-1) were up-regulated in the cholinergic phenotype, which could be dose-dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP(+) or rotenone-induced reactive oxygen species generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1-3 h after exposure to MPP(+) or rotenone. Taken together, these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone.

Dataset Information

Autophagy Signaling by Neural-Induced Human Adipose Tissue-Derived Stem Cell-Conditioned Medium during Rotenone-Induced Toxicity in SH-SY5Y Cells.

Publications

Autophagy Signaling by Neural-Induced Human Adipose Tissue-Derived Stem Cell-Conditioned Medium during Rotenone-Induced Toxicity in SH-SY5Y Cells.

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