Objective: This study is aimed to investigate the role of astrocytes on the accumulation and propagation of α-synuclein (a-syn), the main component of Lewy bodies/neurites, in human dopaminergic (DA) neurons.

Background: The pathological hallmark of Parkinson’s disease is characterized by the accumulation of α-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, but rarely in glial cells.  Recent evidence suggested that glial cells play an important role in the development of α-syn pathology.  Yet it remains to be determined whether they protect DA neurons from α-syn toxicity.

Method: We differentiated DA neurons and astrocytes from iPS cells derived from normal individuals and carrying mutations in lysosomal ATP13A2/PARK9, a monogenic form of synucleinopathy known as Kufor-Rakeb syndrome (KRS). ATP13A2 encodes a lysosomal Type 5 P-type ATPase and loss of its function results in impaired two exocytotic pathways, exosomes and lysosomal exocytosis, both of which are important to regulate α-syn levels in neurons. We conducted comprehensive studies using these cells.

Results: We found that astrocytes can remove different species of α-syn from the media much faster than neurons. Co-culturing astrocytes were able to attenuate the abnormally elevated a-syn levels in DA neurons by clearing internalized a-syn with higher lysosomal and non-lysosomal proteolytic activities than neurons. Furthermore, co-culturing astrocytes prevent a-syn transfer between neurons.  Importantly, all these protective functions were partially hampered by PARK9 deficiency.

Conclusion: These results highlight the protective role of astrocytes against the accumulation in neurons and propagation between neurons.  Loss of PARK9 in astrocytes, at least partially, contributes to a-syn-mediated PD pathology, suggesting that astrocytic protective functions against a-syn toxicity may be potential targets for developing therapeutics for KRS and other related synucleinopathies such as PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/protective-role-of-astrocytes-on-%ce%b1-synuclein-accumulation-and-propagation/