Asha Abraham

Introduction. Parkinson’s Disease (PD) is a slow neurodegenerative disorder involving dopaminergic neuronal degradation with motor and non-motor symptoms commonly observed in the elderly.¹ Research increasingly proposes a prion-like mechanism in aSyn inclusion propagation through neurons secreting aSyn into the extracellular space, aSyn endocytosis into nearby neurons, and exogenous aSyn oligomerizing with endogenous aSyn, seeding aggregate formation.² Inhibiting transmission may contribute to personalized therapies impairing disease progression by altering the FcgRIIB/SHP-1/2 pathway and through aSyn antibodies clearing fibrils from the extracellular space.³ Methods. Protein misfolding cyclic amplification (PMCA) detected minute amounts of aSyn aggregation in CSF of PD patients, subsequently nucleating further aggregation in an in vitro study involving synthetic aSyn oligomers and blinded patient CSF samples.⁴ Studies involving an in-vitro co-culture system using double fluorescence-labeled cells co-stained with pSer129 aSyn assessed FcgRIIB as a neuronal receptor for aSyn fibrils mediating transmission with contribution from SHP-1/2 activation downstream.³ In-vitro experiments involving cellular model systems with live-cell imaging and flow cytometry quantified aSyn transfer between cultured mouse neurons.⁵ These co-culture systems measured protein uptake through only fluorescent tags or combined them with aSyn.⁵ Transgenic mice were injected with various mutant aSyn fibril strains utilizing recombinant aS purified from E. coli.⁶ Strains were incubated with constant shaking inducing fibril formation.⁶ Mice were assessed for time to paralysis and amount and distribution of inclusions.⁶ Results. aSyn-PMCA allowed for detection of as little as 0.1 pg/mL of oligomers with high overall sensitivity (88.5%) and specificity (96.9%) and correlation with clinical symptom severity.⁴ A co-culture system affirmed FcgRIIB/SHP-1/2 signaling impacts endocytosis of extracellular aSyn through the receptor; FcgRIIB knockdown cell lines indicated lack of fibril interaction and less efficient spread without a template for subsequent misfolding.³ Another in-vitro model system indicated a time-dependent nature in quantifying aSyn intercellular transfer with highest transfer in cells incubated for 5 days as affirmed by live cell imaging.⁵ The cycle of conformational templating of native aSyn proteins was detected from amyloid seeding in mice injected with H50Q, G51D, and A53E fibrils.⁶ However, E46K aS fibril injections indicated decreased pathology, denoting symptom heterogeneity in variant prion strains.⁶ Conclusions. Studies have indicated PMCA technology may serve in monitoring disease progression and preclinical identification before PD symptom development.⁴ Altering the FcgRIIB/SHP-1/2 pathway may serve as a powerful clinical target by deterring cell-to-cell propagation.³ Hence, attempts to impair various components of the aSyn transmission pathway can serve as personalized therapies impeding pathological spread.

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