Dual inhibition of aminoacyl-tRNA synthetase interacting multifunctional protein-2 and α-synuclein by steroid derivative is neuroprotective in Parkinson's model.

Aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2), a parkin substrate, possesses self-aggregating properties, potentiating α-synuclein aggregation and neurotoxicity in PD. Thus, targeting both α-synuclein and AIMP2 would present an effective treatment for PD pathologies. Herein, we developed small compounds with dual inhibitory activity against AIMP2 and α-synuclein.

Metal-enhanced fluorescence biosensor integrated in capillary flow-driven microfluidic cartridge for highly sensitive immunoassays.

Point-of-care testing (POCT) for low-concentration protein biomarkers remains challenging due to limitations in biosensor sensitivity and platform integration. This study addresses this gap by presenting a novel approach that integrates a metal-enhanced fluorescence (MEF) biosensor within a capillary flow-driven microfluidic cartridge (CFMC) for the ultrasensitive detection of the Parkinson's disease biomarker, aminoacyl-tRNA synthetase complex interacting multi-functional protein 2 (AIMP-2). Crucial point to this approach is the orientation-controlled immobilization of capture antibody on a nanodimple-structured MEF substrate within the CFMC.

ATF4-activated parkin induction contributes to deferasirox-mediated cytoprotection in Parkinson's disease.

The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD.

Pharmacological inhibition of AIMP2 aggregation attenuates α-synuclein aggregation and toxicity in Parkinson's disease.

The aggregation of aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2) accelerates α-synuclein aggregation via direct interaction, leading to enhanced dopaminergic neurotoxicity in Parkinson's disease (PD). Thus, it would be beneficial to prevent AIMP2 aggregation to suppress α-synucleinopathy in PD. In this study, we screened small compounds that could inhibit the in vitro aggregation of AIMP2 using a 1909 small-compound library.

Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration.

Aberrant activation of the non-receptor kinase c-Abl is implicated in the development of pathogenic hallmarks of Parkinson's disease, such as α-synuclein aggregation and progressive neuronal loss. c-Abl-mediated phosphorylation and inhibition of parkin ligase function lead to accumulation of parkin interacting substrate (PARIS) that mediates α-synuclein pathology-initiated dopaminergic neurodegeneration. Here we show that, in addition to PARIS accumulation, c-Abl phosphorylation of PARIS is required for PARIS-induced cytotoxicity.

Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson's Disease via a Vitamin D Receptor-Dependent Pathway.

The progressive neurodegeneration in Parkinson's disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biology has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we observed reduced transcription of the VDR and its downstream target genes, and .

Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion.

Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of α-synuclein with associated proteins, such as parkin and its substrate aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2). Although AIMP2 has been suggested to be toxic to dopamine neurons, its roles in α-synuclein aggregation and PD pathogenesis are largely unknown.