SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids [Ribo-seq]

Proteomic and transcriptomic analyses revealed upregulation of cytoskeletal, synaptic, and axonal development pathways, alongside significant downregulation of extracellular matrix (ECM) components and upregulation of perineuronal net (PNN) genes. Ribosome profiling showed minimal global translational changes but uncovered selective translational buffering of neuronal and ECM-associated transcripts. Confocal imaging confirmed progressive disorganization of pericellular and interstitial ECM structures around neurons in SNCA Trip organoids.

Our findings demonstrate that SNCA triplication induces early proteostatic disruption and extracellular matrix remodelling prior to neurodegeneration and suggest that altered gene expression and ECM homeostasis may contribute to disease initiation and progression. Targeting these early aberrant mechanisms may offer new therapeutic opportunities for synucleinopathies, such as Parkinson’s Disease.