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03-07-2011 | Neurology | Article

Gaucher disease pathway offers PD clue


Free abstract

MedWire News:Researchers investigating the molecular pathway that leads to Gaucher disease believe they have hit upon a novel therapeutic approach to Parkinson's disease (PD).

The team was following up reports of a clinical link between Gaucher disease and PD. Patients with Gaucher disease lack functional glucocerebrosidase (GCase), causing them to accumulate glucocerebroside (GlcCer) in their lysosomes.

A subset of Gaucher disease patients display parkinsonian symptoms, and reportedly have Lewy bodies containing α-synuclein (syn), which is typical of PD patients.

Reporting in the journal Cell, the researchers show that, in cultured neurons, reduced lysosomal proteolysis caused by loss of GCase led to a 1.8-fold increase in levels of α-syn. This occurred specifically through the pathway involving GlcGer, rather than being a result of generally reduced lysosomal proteolysis.

Increased α-syn levels were associated with reduced cell viability, with this process dependent upon the formation of high-molecular-weight oligomers of α-syn.

In human brain tissue samples, α-syn profiles were similar in two patients with Gaucher disease and three controls, but the researchers found a "dramatic" increase in oligomeric α-syn species in a tissue from a Gaucher disease patient with parkinsonian symptoms.

In cultured cells, overexpression of α-syn had a knock-on effect on GCase, inhibiting its movement within the cell and leading to further reduced GCase expression within the lysosomes.

"It appears that interaction between α-syn deposition and the Gaucher's pathway forms a feedback loop that eventually leads to self-propagating disease," said lead researcher Dimitri Krainc (Harvard Medical School, Boston, Massachusetts, USA).

Krainc's team found that brain tissue from healthy humans had highly variable levels of α-syn, which correlated with the lysosomal maturation and activity of GCase.

In tissue samples from six patients with idiopthic PD, total GCase levels were about 40% lower than levels in six control individuals matched for age and postmortem time.

"We now propose that therapies targeting glucocerebrosidase activity may help break the vicious cycle of α-syn accumulation and neurodegeneration," said Krainc.

"We think this pathway potentially applies to any disease characterized by α-syn accumulation and are now partnering with industry to develop novel therapies for Parkinson's disease that improve targeting of glucocerebrosidase to lysosomes. We hope that such treatments may prevent or diminish the accumulation of α-syn and resultant neurodegeneration in diseases such as Parkinson's and Dementia with Lewy bodies."

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Eleanor McDermid

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