Abstract
Neurobiology Parkinson's disease (PD) has been clinically linked to a rare lysosomal storage disease known as Gaucher disease (GD). Patients with GD lack the enzyme glucocerebrosidase (GCase), which leads to the accumulation of the glycolipid glucosylceramide. In PD, intracellular accumulation and aggregation of the α-synuclein protein in neurons is a key event in disease pathogenesis. Mazzulli et al. wanted to elucidate the mechanistic link between these two disorders. In neuronal tissue culture systems and in mouse disease models, intracellular accumulation of glucosylceramide compromised lysosomal proteolysis and led to the accumulation of cytotoxic α-synuclein and neurodegeneration. Furthermore, glucosylceramide directly promoted the aggregation of purified α-synuclein in vitro. The accumulation of the α-synuclein itself in neurons also compromised the production of mature, active lysosomal GCase, generating a pathogenic cycle. Analysis of postmortem brain samples from human patients also suggested that GCase deficiencies were often linked to pathological α-synuclein accumulation. Intervention in this pathogenic cycle by increasing the efficiency of GCase targeting to lysosomes may thus represent a future approach toward ameliorating PD and other related diseases. Cell 146 , 37 (2011).
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