Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models

Abstract

Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease

“…GCase is synthesized in the ER and transported by lysosomal integral membrane protein 2 (LIMP2) to the lysosome. Upon reaching the lysosomal lumen, GCase becomes active and hydrolyzes GlcCer to ceramide and glucose (reviewed in [ 11 , 56 ]). The link between GCase deficiency and synucleinopathy was first reported in neuropathological studies of GD patients with parkinsonism, which revealed the presence of LBs and α-syn aggregation in the hippocampus [ 65 , 66 ].…”

“…The ALP is regulated by LRRK2 and GBA along with several other PD-associated genes. Its disturbance is a key mechanism in the pathogenesis of PD (reviewed in [ 11 ]). Since there is strong evidence linking lysosomal dysfunction with α-syn aggregation and propagation, therapeutic strategies to enhance autophagy and improve lysosomal dysfunction are being employed in disease modification of PD.…”

“…Apart from directly modulating enzymatic activities of LRRK2 kinase and GCase, the general abnormalities in ALP as revealed in postmortem PD brain samples as well as cell and animal models suggest that modulation of pathways to enhance autophagy may also be viable therapeutic options. For example, farnesyltransferase inhibitors have been shown to enhance GCase activity, reduce α-syn aggregation and improve neuronal viability in PD patient-derived iPSC-midbrain neurons expressing A53T mutant α-syn by promoting hydrolase trafficking to the lysosome [ 11 , 114 ]. Inhibition of mTOR promotes macroautophagy and ALP, and induces nuclear translocation of transcription factor B (TFEB), thus activating transcription of autophagic and lysosomal proteins [ 11 , 115 ].…”

“…For example, farnesyltransferase inhibitors have been shown to enhance GCase activity, reduce α-syn aggregation and improve neuronal viability in PD patient-derived iPSC-midbrain neurons expressing A53T mutant α-syn by promoting hydrolase trafficking to the lysosome [ 11 , 114 ]. Inhibition of mTOR promotes macroautophagy and ALP, and induces nuclear translocation of transcription factor B (TFEB), thus activating transcription of autophagic and lysosomal proteins [ 11 , 115 ]. Hence, inhibitors of mTOR, such as rapamycin, represent another treatment strategy.…”

“…However, advancements in our understanding of the genetic basis of PD suggest that genetic factors can cause or increase the susceptibility to PD to a much larger extent than previously thought: the heritability of PD has been estimated to be at least 27% and up to 60% in large genome-wide association studies (GWAS) (reviewed in [ 9 ]). Genes and genetic loci identified in familial and sporadic PD are strongly enriched for autosomal/lysosomal functions: among the 24 loci identified by GWAS to be associated with PD [ 10 ], at least 11 genes are implicated in the ALP [ 9 , 11 ]. In particular, mutations in LRRK2 (encoding leucine-rich repeat kinase 2, LRRK2) and GBA (encoding glucocerebrosidase, GCase) are now recognized as two most common genetic causes of PD worldwide [ 9 ].…”