CTSB and Parkinson disease: In parkinsonism, pathological patterns of pyramidal neuronal activity (e.g., enhanced burst firing) and synchronous glutamatergic inputs (e.g., thalamic afferents) are expected to significantly elevate local glutamate concentration (16, 36, 38), which in turn leads to GluN2B-NMDARs overstimulation and the associated signaling cascades (34, 39, 59, 60), such as the ubiquitin-proteasome pathway (59, 61) or cathepsin B-like protease activity that regulates actin-based cytoskeleton to mediate morphological changes (62).