Objective: To evaluate the membrane dynamics and inflammatory profile of astrocytes differentiated from LRRK2-I1371V PD iPSCs in the presence and absence of extracellular α-Synuclein.

Background: LRRK2 stands out as a significant contributor to inherited PD, with its various pathological variants exhibiting distinct ethnic biases in incidence rates. While G2019S mostly is prevalent in Caucasians, the I1371V is common in East Asians, however research on its mechanism is lacking, emphasizing the need to elucidate its specific mechanisms underlying disease pathology. Variation in symptoms and treatment responses highlight the need to comprehend the effect of different mutations on cellular function in PD. Postmortem data have revealed the presence of Lewy bodies in individuals with the I1371V mutation, suggesting distinct pathological processes compared to G2019S cases, involving extracellular α-synuclein accumulation. Astrocytes, crucially clear extracellular α-synuclein however its accumulation can perturb astrocyte function without impacting cell survival, exacerbating α-synuclein-mediated pathology. Given the dependence of dopamine neurons on astrocytic support, compromised astrocyte function could contribute to neurodegeneration and death.

Method: The effect of the mutation on the α-synuclein association in the astrocytes derived from HC and PD astrocytes and how the plasma membrane plays a role in it has been investigated. Additionally, the pathophysiology of extracellular α-synuclein treatment on the HC and PD astrocytes has also been looked into.

Results: Reduced extracellular α-synuclein association and uptake is observed in PD astrocytes due to alterations in membrane cholesterol and fluidity, and ganglioside expression the reason being the increased Rab8A and Rab10 phosphorylation due to the mutation. PD astrocytes shows intrinsic higher ROS and RNS levels which further elevates upon treatment with extracellular α-synuclein contributing to the increased levels of pro- inflammatory cytokines and expression of p-synuclein; and n-synuclein respectively, however the cell viability is not affected.

Conclusion: The decreased association of α-synuclein in PD astrocytes, alongside reduction in cholesterol levels and membrane fluidity, highlights pathophysiology in PD, underscoring the importance of unraveling variant-specific impacts on cellular function.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-lrrk2-i1371v-mutation-alters-membrane-dynamics-and-inflammatory-profile-of-astrocytes-differentiated-from-lrrk2-i1371v-pd-patient-ipscs/