Researchers have shown that defective versions of human brain cells called astrocytes are linked to the buildup of a toxic protein that is the hallmark of Parkinson's disease. The studied astrocytes, derived from Parkinson's disease patients with a genetic mutation that affects cell clean-up functions, caused more accumulation of the toxin, alpha-synuclein, than those derived from healthy individuals. The work, which appears January 10 in the journal Stem Cell Reports, suggests an important role for glial cells in Parkinson's disease and offers potential new targets for developing therapies.
"Our overall results completely turn our previous view of the participation of astrocytes in Parkinson’s disease upside down," says Antonella Consiglio of the IDIBELL and University of Barcelona, co-senior author on the study with Angel Raya of the Center of Regenerative Medicine in Barcelona. "From mainly bystander cells with some early protective role, we believe they should now be considered as critical players that spread the disease and amplify the degree of neuronal degeneration."
Known as support cells in the brain, astrocytes extend branching tendrils around synapses and along blood vessels. One previous postmortem study found that Parkinson's patients had an abnormal buildup of alpha-synuclein--a protein that accumulates to form Lewy bodies, the signature pathology of Parkinson's disease--in their neurons as well as their astrocytes. While this this was interpreted by most researchers as a secondary response, as if astrocytes were trying to clear up alpha-synuclein aggregates from neurons, it led the researchers to examine astrocytes' role in the disease.
The researchers generated stem-cell-derived glia cells using cells derived from Parkinson's patients with an LRRK2 mutation. Fifteen percent of Parkinson's cases are tied to an inherited gene mutation, and 7 percent of all cases--inherited and sporadic--are linked to a large protein complex called LRRK2. LRRK2's main function is still unknown, but it seems to play a role in mitochondrial dynamics and autophagy, a process through which cells break down and rebuild their damaged components.
The researchers then used CRISPR/Cas9 gene editing technology to tag and track the toxic alpha-synuclein as it was generated by the stem-cell-derived astrocytes and transferred to dopamine-producing neurons.
"We found Parkinson's disease astrocytes to have fragmented mitochondria, as well as several disrupted cellular degradation pathways, leading to the accumulation of alpha-synuclein," says co-first author Angelique di Domenico, former postdoctoral fellow at the University of Barcelona's Bellvitge Biomedical Research Institute.
The accumulation of alpha-synuclein caused the targeted neurons' projecting branches--axons and dendrites--to shorten and disintegrate, resulting in neuronal death, she says.
"In contrast, healthy astrocytes exerted a positive effect on neurons from Parkinson's disease patients, protecting them from undergoing cell death," says Consiglio. "Upon further investigation, we found Parkinson's disease astrocytes to have disruption in several cellular degradation pathways, causing the consequent accumulation of endogenous astrocyte-derived alpha-synuclein.
The researchers used a drug--developed to treat abnormal intracellular buildup of toxic materials--on the Parkinson's disease astrocytes. "We were elated to see after treatment that the cellular degradation processes were restored and alpha-synuclein was completely cleared from the Parkinson's disease astrocytes," di Domenico says.
The researchers next plan to investigate astrocytes from the 85 to 90 percent of Parkinson's cases that are sporadic, with no known genetic cause. "While these results pave the way to using astrocytes as a target for novel therapies, there is much to be learned before these treatments can be translated to human beings," says Consiglio.
For more information on this study, please visit: http://www.idibell.cat/en/whats-on/noticies/defective-glial-cells-can-push-neurons-toward-parkinsons-disease
This work was supported by the European Research Council-ERC, the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, AGAUR, and CERCA Programme / Generalitat de Catalunya.
Stem Cell Reports, di Domenico et al.: "Patient-specific iPSC-derived astrocytes contribute to non-cell autonomous neurodegeneration in Parkinson's disease" https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(18)30530-7
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