神经损伤与修复
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Figure 1 ｜ Effects of secreted neuronal α-synuclein (α-Syn) species on different glial cells in the context of lysosomal pathways.
Next to proteasomal processing, α-Syn can also get degraded via autophagy within neuronal cells. Recent studies implicate the lysosomal proteases cathepsin D (CTSD), cathepsin B (CTSB), and cathepsin L in the degradation of α-Syn. Additionally, impairments in the lysosomal degradation pathway or enzyme dysfunction can lead to the aggregation of α-Syn. Hence, diseaseassociated CTSD variants were shown to be impaired in their maturation and exhibited altered α-Syn degradation properties in human cell models (Bunk et al., 2021). Furthermore, it is known that mutations within the gene encoding for the lysosomal enzyme β-glucocerebrosidase (GBA1) (Figure 1) present a common genetic risk factor for the development of PD. GBA1 gene mutations in PD patients lead to an insufficient degradation of its substrate glucosylceramide in lysosomes, which has been shown to interfere and accelerate α-Syn aggregation (Zunke et al., 2018). Interestingly, the aggregation of α-Syn also contributes to further lysosomal dysfunction, probably by interrupting lysosomal protein trafficking. Genetic studies have associated further genes linked to lysosomal function, like the lysosomal hydrolases CTSD and CTSB, the cation-transporting ATPase 13A2 (ATP13A2) or vacuolar protein sortingassociated protein 35 (VPS35) to an increased risk of developing PD (Figure 1), indicating the importance of lysosomal function in neuronal homeostasis (Puska et al., 2018; Zunke et al., 2018).