Abstract
Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson’s disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson’s disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.
Highlights
Lysosomes are subcellular acidic vesicles containing acid hydrolases
Parkinson’s disease (PD)-linked disease mutations are found in the amphipathic region, and it is known that sphingolipid metabolites that accumulate in lysosomal storage diseases (LSD) can interact with α-synuclein and induce its aggregation, which suggests that the interaction between α-synuclein and lipids plays an important role in PD pathogenesis and partially explains the selectivity of α-synuclein aggregation when lipid degradation is altered [28,47,48]
LSDs with PD: (1) neurodegeneration is one of the main features of LDSs [2]; (2) parkinsonism has been reported in some patients with different LSDs [151,156,157]; (3) an increased risk of PD has been well established in Gaucher’s disease [39,40], and it has been suggested in Fabry disease [152]; and (4) aggregation of α-synuclein has been reported in the brain of patients and animal models of different LSDs, including Gaucher’s disease [158], Fabry disease [92], Niemann-Pick disease [159,160], Sandhoff disease, Tay-Sachs disease, metachromatic leukodystrophy, β-galactosialidosis and GM2 gangliosidosis [161], Krabbe disease [162], and neuronal ceroid-lipofuscinosis [163]
Summary
Lysosomes are subcellular acidic vesicles containing acid hydrolases. The main function of these organelles is the degradation of intracellular and extracellular macromolecules that are broken down into their primary constituents to be further recycled in the cytosol with the aim of building new cellular components. Cells 2020, 9, x sclerosis (ALS), and several others have lysosomal dysfunction as one of the molecular pathways involved in sclerosis their etiology and several development. Thislysosomal bidirectional link between neurodegeneration lateral (ALS), and others have dysfunction as one of the molecular and lysosomal dysfunction emphasizes of lysosomal functionlink in maintaining pathways involved in their etiologythe andimportance development. This bidirectional between neuronal homeostasis. and lysosomal dysfunction emphasizes the importance of lysosomal function in neurodegeneration maintaining neuronal homeostasis
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