Lysosomal Dysfunction and α‐Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Abstract

Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.

The Coordinated Action of Calcineurin and Cathepsin D Protects Against α-Synuclein Toxicity

“…General lysosomal dysfunction as well as alterations in CatD levels and activity are implicated in the pathogenesis of PD (Qiao et al, 2008; Sevlever et al, 2008; Manzoni and Lewis, 2013; Matrone et al, 2016; Moors et al, 2016). To further analyze the impact of αSyn on lysosomal integrity in general and on CatD function in particular, we used a yeast model for PD based on the heterologous expression of human αSyn.…”

Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein

“…Higher order oligomeric α-syn species are degraded by macroautophagy while monomeric and dimeric species are degraded by chaperone mediated autophagy or by the ubiquitin proteasome system 35 . However, it has been established that aggregation prone mutants of α-syn, over-expression of α-syn and LB-like α-syn inclusions inhibit autophagy, resulting in a vicious cycle where α-syn degradation is impaired, leading to larger aggregates and eventually cell death 36 . Furthermore, in order to maintain cellular homeostasis, the inhibition of autophagy also leads to an increase in exocytosis 37–39 .…”

Genetic risk factors in Parkinson’s disease

“…In support of this theory, the last decade has witnessed an increasing amount of genetic evidence implicating the lysosomal system as a central mechanism in the pathobiology of PD (Kalia and Lang 2015; Moors et al 2016; Vekrellis et al 2011; Wong and Krainc 2016). As previously described, heterogeneous mutations in GBA confer high risk for PD, and pathogenic variants in ATP13A2 , encoding a lysosomal ATPase, are responsible for a very rare cause of parkinsonism (Park et al 2015).…”