» Articles » PMID: 30639209

Patient-Specific IPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease

Abstract

Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

Citing Articles

New perspectives on heterogeneity in astrocyte reactivity in neuroinflammation.

Santos D, Silva Lima S, Moreira L, Costa S, de Sampaio Schitine C Brain Behav Immun Health. 2025; 44:100948.

PMID: 40028234 PMC: 11871470. DOI: 10.1016/j.bbih.2025.100948.


Canonical and noncanonical autophagy: involvement in Parkinson's disease.

Sakurai M, Kuwahara T Front Cell Dev Biol. 2025; 13:1518991.

PMID: 39949604 PMC: 11821624. DOI: 10.3389/fcell.2025.1518991.


Two- and Three-Dimensional In Vitro Models of Parkinson's and Alzheimer's Diseases: State-of-the-Art and Applications.

Solana-Manrique C, Sanchez-Perez A, Paricio N, Munoz-Descalzo S Int J Mol Sci. 2025; 26(2).

PMID: 39859333 PMC: 11766061. DOI: 10.3390/ijms26020620.


Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.

Liu M, Liu S, Lin Z, Chen X, Jiao Q, Du X Biomolecules. 2025; 15(1).

PMID: 39858542 PMC: 11764135. DOI: 10.3390/biom15010149.


LRRK2 G2019S Mutated iPSC-Derived Endothelial Cells Exhibit Increased α-Synuclein, Mitochondrial Impairment, and Altered Inflammatory Responses.

Sonninen T, Peltonen S, Niskanen J, Hamalainen R, Koistinaho J, Lehtonen S Int J Mol Sci. 2024; 25(23).

PMID: 39684585 PMC: 11641647. DOI: 10.3390/ijms252312874.


References
1.
Park C, Suh Y, Cuervo A . Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat Commun. 2015; 6:6823. PMC: 4400843. DOI: 10.1038/ncomms7823. View

2.
Lee H, Suk J, Patrick C, Bae E, Cho J, Rho S . Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010; 285(12):9262-72. PMC: 2838344. DOI: 10.1074/jbc.M109.081125. View

3.
Anguiano J, Garner T, Mahalingam M, Das B, Gavathiotis E, Cuervo A . Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat Chem Biol. 2013; 9(6):374-82. PMC: 3661710. DOI: 10.1038/nchembio.1230. View

4.
Gu X, Long C, Sun L, Xie C, Lin X, Cai H . Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain. 2010; 3:12. PMC: 2873589. DOI: 10.1186/1756-6606-3-12. View

5.
Fu L, Gao Y, Tousson A, Shah A, Chen T, Vertel B . Nuclear aggresomes form by fusion of PML-associated aggregates. Mol Biol Cell. 2005; 16(10):4905-17. PMC: 1237092. DOI: 10.1091/mbc.e05-01-0019. View