The Emerging Role of the Lysosome in Parkinson’s Disease

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.

Proteome Profiling of Cerebrospinal Fluid Reveals Novel Biomarker Candidates for Parkinson’s Disease

“…To examine if PD affects particular cellular compartments and biological networks in CSF, we performed a Gene Ontology (GO) annotation enrichment analysis using the mean fold-changes of PD vs. HC [37]. The proteins elevated in the PD samples compared to the controls were enriched for categories related to lysosomal terms, further supporting the emerging role of lysosomes and mounting evidence for lysosomal dysregulation and associated a-synuclein aggregation in PD [13, 38, 39] ( Figure 3F ).…”

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…Genetic and post-mortem studies have suggested that modifications occur in both macroautophagy and CMA in the case of PD [39]. Mutations or posttranslational modifications of SYN can also affect its turnover by CMA, such as the A30P and A53T mutants, related to familial cases of PD, which are not efficiently degraded through CMA, they can bind LAMP-2A, but are not internalized inside the lysosomes [40]. The protein level of the LAMP-2A, a key CMA marker, can be decreased in the substantia nigra of PD brains as compared to controls [41], while its protein level correlates with increased SYN accumulation in the affected PD brain regions.…”

“…In recent years, emerging evidence points out that microglial and astrocytic dysfunction may also play an important role in the pathogenesis of PD [40]. Several genes associated with PD are also expressed in glial cells, displaying comparable or even higher levels than in neurons, which are also involved in inflammatory response, oxidative stress, lysosomal and mitochondrial function, and autophagy.…”

“…Since neuronal cells are highly polarized, they require a highly specialized and complex endocytic machinery. Alterations in this complex system have also been described in PD [40]. Besides conventional endocytosis, exosomal transport, receptor-mediated internalization, passive diffusion, or even direct penetration of the plasma membrane have been suggested as possible pathways for SYN uptake [98].…”

LRRK2 at the Crossroad of Aging and Parkinson’s Disease

“…Several pathogenic LRRK2 mutant models, including neuronal cell lines, primary cortical neurons and astrocytes, and Tg animal models, have reported abnormal lysosomal phenotypes, such as abnormal morphology [ 16 , 150 , 151 , 152 , 153 ], altered pH [ 154 , 155 ], and diminished activity [ 16 , 154 ]. Primary cortical neurons overexpressing LRRK2 G2019S or LRRK2 I2020T contained multivesicular bodies (MVBs) and swollen lysosomes [ 156 ].…”