Authors
Indrani Datta, Dibyam Debasish Sahu
Published in
Advances in immunology. Volume 171. Pages 215-246. Epub Jun 16, 2026.
Abstract
Parkinson's disease (PD) pathology extends well beyond dopaminergic neuronal loss, with glial cells-microglia and astrocytes-emerging as active architects of α-synuclein spread rather than passive bystanders. This review synthesises current evidence on how mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), the most common genetic cause of familial PD, fundamentally corrupt glial handling of extracellular α-synuclein. We first outline the biology of extracellular α-synuclein-its cellular sources, conformational spectrum, prion-like propagation mechanisms, and principal glial clearance routes-before examining LRRK2 domain architecture, its downstream Rab GTPase signalling cascade, and the cellular processes it governs in glia. We then detail how LRRK2 mutations reconfigure microglial responses: driving constitutive NLRP3 inflammasome priming, impairing phagolysosomal degradation of α-synuclein aggregates, and redirecting phagocytosed cargo into pathogenic exosomal release via the LRRK2-Rab10-LYTL axis. In astrocytes, LRRK2 mutations disrupt annexin A2-mediated phagocytosis, impair chaperone-mediated autophagy and lysosomal acidification, deplete membrane cholesterol through Rab8A/Rab10 hyperphosphorylation, compromise glutamate transporter surface expression, and promote the secretion of phospho-α-synuclein-enriched extracellular vesicles that are neurotoxic to co-cultured dopaminergic neurons. Crucially, dysfunctional microglia and astrocytes do not operate independently-they form a self-amplifying feed-forward circuit in which microglial cytokines (IL-1α, TNF-α, C1q) drive A1 astrocyte conversion, tunnelling nanotube-mediated aggregate exchange propagates rather than resolves α-synuclein burden, and successive waves of neuronal death perpetuate the cycle. We highlight that these mechanisms are mutation-specific: the GTPase-domain variant I1371V, characterised through our group's patient-derived iPSC platform, drives qualitatively distinct membrane and metabolic dysfunction compared with the kinase-domain variant G2019S, underscoring the need for variant-tailored therapeutic strategies. We review human iPSC-based models-including microglia-like cells, midbrain-patterned astrocytes, and 3D midbrain organoids-that have proven indispensable for resolving cell-autonomous from non-cell-autonomous contributions of LRRK2 mutations. Finally, we evaluate emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement, including intranasal mesenchymal stromal cell-derived small extracellular vesicles. We conclude by identifying key unanswered questions regarding the relative dominance of microglial versus astrocytic clearance at different disease stages, the full pathogenic landscape of understudied LRRK2 variants, and the tractability of glial biomarkers as pharmacodynamic endpoints in clinical trials.
PMID:
42629126
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 10
- Comments 0