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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model

Gustavo Morrone Parfitt, Elena Coccia, Camille Goldman, Kristen Whitney, Ricardo Reyes, Lily Sarrafha, Ki Hong Nam, Drew Jones, John F Crary, Alban Ordureau, Joel Blanchard, Tim D Ahfeldt
doi: https://doi.org/10.1101/2022.08.26.505472
Gustavo Morrone Parfitt
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD
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Elena Coccia
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD
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Camille Goldman
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
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Kristen Whitney
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
5Department of Neurology at Mount Sinai, New York, NY, USA
6Department of Pathology, Molecular, and Cell-Based Medicine at Mount Sinai, New York, NY, USA
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Ricardo Reyes
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
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Lily Sarrafha
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
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Ki Hong Nam
7Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Drew Jones
8Metabolomics Core Resource Laboratory, NYU Langone Health, New York, NY, USA
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John F Crary
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
5Department of Neurology at Mount Sinai, New York, NY, USA
6Department of Pathology, Molecular, and Cell-Based Medicine at Mount Sinai, New York, NY, USA
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Alban Ordureau
7Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Joel Blanchard
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD
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  • For correspondence: tim.ahfeldt@mssm.edu
Tim D Ahfeldt
1Nash Family Department of Neuroscience at Mount Sinai, New York, NY, USA
2Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, New York, NY, USA
3Friedman Brain Institute at Mount Sinai, New York, NY, USA
4Black Family Stem Cell Institute at Mount Sinai, New York, NY, USA
9Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD
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  • For correspondence: tim.ahfeldt@mssm.edu
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Abstract

Accumulation of advanced glycation end products (AGEs) on biopolymers accompany cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early on-set Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. These processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in PD.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† Co-senior authors

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Posted August 27, 2022.
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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model
Gustavo Morrone Parfitt, Elena Coccia, Camille Goldman, Kristen Whitney, Ricardo Reyes, Lily Sarrafha, Ki Hong Nam, Drew Jones, John F Crary, Alban Ordureau, Joel Blanchard, Tim D Ahfeldt
bioRxiv 2022.08.26.505472; doi: https://doi.org/10.1101/2022.08.26.505472
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Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model
Gustavo Morrone Parfitt, Elena Coccia, Camille Goldman, Kristen Whitney, Ricardo Reyes, Lily Sarrafha, Ki Hong Nam, Drew Jones, John F Crary, Alban Ordureau, Joel Blanchard, Tim D Ahfeldt
bioRxiv 2022.08.26.505472; doi: https://doi.org/10.1101/2022.08.26.505472

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