Application of SINEUPs treatment against 𝜶-Synuclein aggregates toxicity.

Progressive neuronal loss, neuroinflammation and defective degradation pathways observed in some neurodegenerative disorders are largely attributed to toxic aggregates of α-Synuclein (α-Syn), a small soluble cytosolic protein highly expressed in the central nervous system. Collectively, these diseases are defined as Synucleinopathies, encompassing pathologies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA). Currently, no disease-modifying therapies are available for Synucleinopathies, underscoring the urgent need to focus on promising molecular pathways that could potentially counteract a-Syn aggregation. In this study, we employ SINEUPs, long non-coding RNAs that enhance the expression of specific target proteins without altering the endogenous mRNAs levels, both in vitro and in vivo, as a novel therapeutic strategy for PD. Our aim is to reduce α-Syn toxicity by exploiting SINEUPs-mediated protein upregulation to mitigate chronic inflammation and increase autophagic flux, thereby preserving cellular homeostasis. Here, we show that SINEUPs effectively impact α-Syn accumulation, thus providing protective physiological effects, consistent with a healthier neuronal phenotype. Finally, this study provides the basis for potential clinical applications of SINEUPs and highlights the importance of neuroinflammation and lysosomal-dependent clearance in the context of α-Syn toxicity.