Liu et al. (2021) show and postulate that these autophagic indicators may be regulated by GRN via high mobility group box 1 (HMGB1), a protein that is upstream of the MAPK/ERK pathway and is suppressed by GRN, which negatively modulates autophagy (Figure 2). As GRN is known to be a protective biomolecule in the context of several neurodegenerative diseases, GRN may be asserting its protective effect against excitotoxicity within the autolysosomal pathway despite being an extracellular protein (Davis et al., 2021; Terryn et al., 2021). This evidence concerns the gene HMGB1 and neurodegenerative disease.