Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model

Gustavo Morrone Parfitt (), Elena Coccia, Camille Goldman, Kristen Whitney, Ricardo Reyes, Lily Sarrafha, Ki Hong Nam, Soha Sohail, Drew R. Jones, John F. Crary, Alban Ordureau, Joel Blanchard () and Tim Ahfeldt ()
Additional contact information
Gustavo Morrone Parfitt: Nash Family Department of Neuroscience at Mount Sinai
Elena Coccia: Nash Family Department of Neuroscience at Mount Sinai
Camille Goldman: Nash Family Department of Neuroscience at Mount Sinai
Kristen Whitney: Nash Family Department of Neuroscience at Mount Sinai
Ricardo Reyes: Nash Family Department of Neuroscience at Mount Sinai
Lily Sarrafha: Nash Family Department of Neuroscience at Mount Sinai
Ki Hong Nam: Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Soha Sohail: Nash Family Department of Neuroscience at Mount Sinai
Drew R. Jones: NYU Langone Health
John F. Crary: Nash Family Department of Neuroscience at Mount Sinai
Alban Ordureau: Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
Joel Blanchard: Nash Family Department of Neuroscience at Mount Sinai
Tim Ahfeldt: Nash Family Department of Neuroscience at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset 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. We demonstrated 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 a DJ1 loss-of-function PD model.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-44732-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44732-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-44732-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().