Decelerated neurodegeneration after intravitreal injection of α-synuclein antibodies in a glaucoma animal model

Abstract

Although elevated intraocular pressure (IOP) remains the major risk factor in glaucoma, neurodegenerative processes continue despite effective IOP lowering. Altered α-synuclein antibody (Abs) levels have been reported to play a crucial role. This study aimed at identifying whether α-synuclein Abs are capable to decelerate neuronal decay while providing insights into proteomic changes. Four groups of Sprague Dawley rats received episcleral vein occlusion: (1) CTRL, no intravitreal injection, n = 6, (2) CTRL IgG, intravitreal injection of unspecific IgG, n = 5, (3) Buffer, intravitreal injection of buffer, n = 6, (4), α-synuclein Ab, intravitreal injection of α-synuclein Ab, n = 5. IOP and retinal nerve fiber layer thickness (RNFLT) were monitored and immunohistochemistry, microarray and proteomic analysis were performed. RNFLT was reduced in CTRL, CTRL IgG and Buffer group (all p < 0.01) and α-synuclein Ab group (p = 0.17). Axon and RGC density showed an increased neurodegeneration in CTRL, CTRL IgG and Buffer group (all p < 0.01) and increased neuronal survival in α-synuclein Ab group (p = 0.38 and 0.06, respectively) compared with fellow eyes. Proteomic analysis revealed alterations of cofilin 1 and superoxide dismutase 1 expression. This data indicate that α-synuclein Ab might indirectly modulate the actin cytoskeleton organization and negatively regulate apoptotic processes via cofilin 1 and superoxide dismutase 1.

Synthetic Polyclonal-Derived CDR Peptides as an Innovative Strategy in Glaucoma Therapy

“…Interestingly, many of these auto-reactivities show a high degree of congruence in sera as well as aqueous humor of glaucoma patients [13,14], and also remain remarkably stable between different study populations [12]. Besides the great potential of these immune-related biomarker candidates for diagnostic applications [14], we have also provided important evidence for the neuroprotective effects of various AAB molecules (e.g., against GFAP, 14-3-3, α-and γ-synuclein) on RGCs in in vivo and ex vivo glaucoma models [15,16,17,18,19]. These findings underline the important therapeutic potential of AABs found in low abundant titers in glaucoma patients and could also serve as an additional treatment option in glaucoma therapy in combination with IOP-lowering medications.…”

Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

“…Additional work with primary hippocampal neurons confirmed a negative effect of pathologic αSyn on actin dynamics, mediated by cofilin-1 inactivation, which impacted on neuronal functions such as axon elongation and migration (Tilve et al, 2015). Additionally, and also supporting αSyn-induced cofilin-1 inactivation, in a glaucoma animal model, consisting on elevated intraocular pressure which results in retinal neurodegeneration, the intravitreal injection of αSyn antibodies hampered neurodegeneration, an effect that was suggested to involve upregulation of cofilin-1 (Teister et al, 2017).…”

Hydrogen Sulfide and β-Synuclein Are Involved and Interlinked in the Aging Glaucomatous Retina

“…Treatments targeting SNCA to reduce its levels and toxicity have shown positive results in rescuing neuronal cells and halting the neurodegeneration process in preclinical studies [56,60]. For example, in our previous study, intravitreal injection of SNCA antibodies is found to be neuroprotective in a glaucoma animal model [31].…”

“…In our previous work, we demonstrated that exogenous H 2 S supplement and α-synuclein antibodies significantly improved the RGC survival in different experimental glaucoma [19,31]. However, the underlying mechanisms remained to be explored.…”

“…Synucleins are present in the retina and optic nerve [28] and are associated with glaucomatous alterations in the optic nerve [29]. SNCA autoantibody was found to be downregulated in serum and upregulated in aqueous humor of glaucoma patients [30], and in our previous study, intravitreal injection of SNCA antibodies is found to be neuroprotective in a glaucoma animal model [31]. β-Synuclein shares a similar protein structure to SNCA [32], but lacks the nonamyloid-β component domain [33].…”