LAUSR

Lysosomes are cellular organelles with multiple functions that are important in the maintenance of cellular homeostasis. Specifically, lysosomes are primarily catabolic stations that degrade both intracellular contents, including through autophagy, and extracellular contents trafficked through endocytosis. Lysosomes can also exert a metabolic sensor role through the LYsosomal NUtrient Sensing machinery that is able to detect amino acids, energy, or growth factors and initiate a downstream catabolic or anabolic response based on nutrient availability. Finally, through lysosomal exocytosis, lysosomes release proteases including cathepsin B to remodel neuronal dendritic spines and also replace and repair the plasma membrane. Perhaps unsurprisingly, lysosomal defects are nominated as a common denominator in multiple neurodegenerative disorders, including Parkinson’s disease (PD). Through genetic analyses, several monogenic mutations (ATP16A2, ATP6AP2) and risk factors (including GBA, SCARB2, GALC, TMEM175, CTSB, and others) that encode for lysosomal proteins have been nominated as contributing to the risk of disease. Among these, GBA is of particular interest as inheriting homozygous mutations causes the pediatric condition Gaucher’s disease but carrying a single heterozygous variant increases the risk of PD by about twofold to threefold. GBA variants also lower age at onset and accelerate disease progression for PD. GBA encodes for glucocerebrosidase (GCase), a lysosomal enzyme that is able to convert glucosylceramide into ceramide and glucose in the lysosomal lumen. Therefore, GCase deficiency leads to an accumulation of glucosylceramide and a deficiency of ceramide. It has been widely reported that PD-linked GBA mutations result in reduced GCase activity, accompanied by decreased lysosomal activity and intracellular ɑ-synuclein accumulation. In the current issue of Movement Disorders, Sanyal and colleagues study the effect of a PD-associated GBA mutation (p.D409V) in mouse primary astrocytes where, importantly, the mutation is knocked in to the mouse germline and thus is expressed at the endogenous level. In contrast to many prior studies, Sanyal and colleagues focused their studies not on neurons but on glial cells, likely as an increasing amount of evidence points toward the participation of nonneuronal cells in the pathobiology of PD. Specifically, astrocytes were used in this study as these cells play critical roles in the physiological support of neuronal function and survival. Interestingly, senescent markers are preferentially present in the astrocytes in brain PD samples, and the depletion of senescent astrocytes is protective in a toxin-based mouse model of PD. Disease-linked astrocytes may also contribute to dopaminergic neuron toxicity in a noncell autonomous fashion. Several known genes for PD, including GBA, show enriched expression in astrocytes (http://www.brainrnaseq.org). In addition, a second relatively common gene for familial PD that has also been implicated in sporadic disease, leucinerich repeat kinase 2 (LRRK2), is also expressed in the same cell type. Importantly for understanding the work of Sanyal and colleagues, pathogenic mutations in this gene increase its cellular kinase activity and therefore, by logical extension, kinase inhibitors are currently being considered as therapeutic agents for PD. Sanyal and colleagues used astrocytes carrying the GBA p.D409V mutation knocked in to the endogenous murine locus. As expected, the cells from these animals have lower GCase activity although total GCase levels remain unaltered, suggesting a possible retention of the protein in a prelysosomal compartment, as previously reported in fibroblasts isolated from PD patients harboring the GBA-N370S mutation. The authors then cataloged lysosomal activity using a number of different © 2020 International Parkinson and Movement Disorder Society