Magic shotgun for Parkinson’s disease?

In this issue of Brain , two articles explore the intriguing relationship between mutations in the lysosomal enzyme glucocerebrosidase (GBA) and Parkinson’s disease. Siebert et al. (2014) present a comprehensive review of the strong evidence for a connection between autophagy-lysosomal dysfunction and neurodegeneration in Parkinson’s disease, while McNeill et al. (2014) provide experimental evidence suggesting that this connection is a plausible target for disease-modifying therapy.It is a truism that developing effective disease-modifying treatments for neurodegenerative diseases is difficult, with many obstacles to achieving success. Effective treatments must, for example, penetrate the blood–brain barrier with favourable pharmacokinetic properties, and gain access to therapeutic targets that are mostly located intracellularly. Despite the best efforts of both bench and clinical researchers, we seem a considerable distance away from possessing disease models with strong predictive validity. In Parkinson’s disease, model development has been particularly frustrating. Identification of several Mendelian forms of parkinsonism has not led to the development of murine genetic models with strong face validity. Moreover, research over the last couple of decades has revealed features of neurodegeneration that pose additional obstacles, requiring conceptual adjustments in the approach to the development of disease modifying therapies.Our thinking has been dominated by descendants of Paul Ehrlich’s ‘Magic Bullet’ concept (Yarnell, 2005). Find a key node in a well defined pathological cascade, target it with an effective small molecule, and cure disease. This approach was spectacularly successful for anti-bacterial chemotherapy and has had modest successes for cancer treatment. The great success of anti-bacterial chemotherapy, however, results from marked differences in the biochemistry …