2026· Advances in Immunology· Vol 171, pp.
215-246
· 0 citations
Medicine
TL;DR
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 and evaluates emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement.
A model in which α-syn oligomer spreading, amplified by aging, simultaneously disrupts the astrocyte–glutamatergic neuron axis and drives microglia into a senescent DAM-like state is proposed, and candidate gene sets for both processes are provided for further investigation of glial dysfunction in PD.
It is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis, and potential treatment modalities include small molecules targeting lysosome function, CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein.
Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad et al.· Neuromolecular medicine· 0 citations
PrPC expression levels are identified as an important modulator of nigrostriatal vulnerability and neuroinflammatory phenotype in response to αSynO, supporting the hypothesis that PrPC contributes to αSynO-mediated pathogenic mechanisms.
Flavio de Souza Júnyor, F. Leser, Sarah de Souza Albuquerque et al.· Frontiers in Neuroscience· 0 citations
This study identifies a subtype of human microglia capable of removing intraneuronal aggregates and potential therapeutic targets and identifies a cluster of disease-associated microglia responsible for this beneficial phenotype and the Parkinson's disease GWAS candidate glycoprotein nonmetastatic melanoma protein B (G...
Hung-Ju Chueh, Antigoni Katsikoudi, Ana Aragón-González et al.· Science Translational Medici...· 0 citations
Alzheimer's disease (AD) is characterized not only by amyloid-β and tau pathology but also by progressive failure of multicellular homeostasis. The P2X7 receptor (P2X7R), a low-affinity ATP-gated ion channel preferentially activated in extracellular ATP-rich pathological microenvironments, is well positioned to transla...
Results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that aquaporin-4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy body dementia and Parkinson's disease.
Molly Braun, Matthew J. Simon, Jay Jang et al.· Brain Communications· 0 citations
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