Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

Abstract

The principal hallmark of Parkinson’s disease (PD) is the selective neurodegeneration of dopaminergic neurones. Mounting evidence suggests that astrocytes may contribute to dopaminergic neurodegeneration through decreased homeostatic support and deficient neuroprotection. In this study, we generated iPSC-derived astrocytes from PD patients with LRRK2(G2019S) mutation and healthy donors of the similar age. In cell lines derived from PD patients, astrocytes were characterised by a significant decrease in S100B and GFAP-positive astrocytic profiles associated with marked decrease in astrocyte complexity. In addition, PD-derived astrocytes demonstrated aberrant mitochondrial morphology, decreased mitochondrial activity and ATP production along with an increase of glycolysis and increase production of reactive oxygen species. Taken together, our data indicate that astrocytic asthenia observed in patient-derived cultures with LRRK2(G2019S) mutation may contribute to neuronal death through decreased homeostatic support, elevated oxidative stress and failed neuroprotection.

Therapeutic Potential of Astrocyte Transplantation

“…Despite α-synuclein being a predominantly neuronal protein, α-synuclein aggregates in other cell types including astrocytes have been reported 148 , and specific upregulation of α-synuclein was seen in astrocytes derived from patient iPSCs carrying LRRK2 mutation (kinase involved in autophagy and associated with an autosomal dominant form of PD) 155 . Astrocytes carrying LRRK2 mutations that were derived from patient iPSC lines also showed decreased astrocytic marker expression and complexity, and these cells produced higher levels of ROS 159 . In addition to the cell-autonomous changes in PD astrocytes, these cells are capable of taking up the misfolded α-synuclein from neurons through endocytosis 160 – 163 , which can result in pathological activation of the former 164 .…”

Immunosuppressive tocilizumab prevents astrocyte induced neurotoxicity in hiPSC-LRRK2 Parkinson’s disease by targeting receptor interleukin-6

“…However, the exact mechanisms involved remain unknown. L2-PD astrocytes display atrophic morphology and altered mitochondrial function (18), 4 metabolic alterations (19), decreased capacity to internalize α-syn (20) and downregulated genes involved in extracellular matrix (21). Yet, whether those physiopathological alterations in L2-PD astrocytes are the cause or a consequence of the disease and whether astrocyte play a role in idiopathic forms of PD impacting on neuronal survival is unknown.…”

“…However, the exact mechanisms involved remain unknown. L2-PD astrocytes display atrophic morphology and altered mitochondrial function (18), (which was not certified by peer review) is the author/funder. All rights reserved.…”