GBA Mutations & Parkinsons
Dimitri Krainc M.D. PhD

The recurrent observation of accumulation and aggregation of mutant proteins in different neurodegenerative disorders indicates the possibility of a shared pathogenic mechanism. Recent data suggest that elimination of mutant protein accumulation can lead not only to a halt of symptomatic progression but also to regression of the disease.

The evidence in Parkinson’s disease (PD) is most compelling since the clinical and genetic studies point to a clear dosage relationship between accumulations of alpha-synuclein and disease.  For example, subtle alterations in expression level of alpha-synuclein are sufficient to cause a wide spectrum of disease phenotypes.

These findings indicate that if alpha-synuclein can somehow be cleared, the disease can be prevented or even reversed.   The clearance of aggregation-prone proteins such as alpha-synuclein is largely achieved through the autophagy-lysosomal system.   However, one of the main challenges is to identify specific mechanisms and targets involved in the clearance of these proteins in order to develop specific therapeutics.    One strategy to tackle this challenge is to examine rare lysosomal storage disorders (LSDs) that commonly exhibit neurodegeneration and are caused by mutations in genes involved in lysosomal function.

Recent clinical and genetic evidence has identified an interesting link between lysosomal storage disorders and neurodegeneration. The best example of this is the linkage between Gaucher disease (GD) and parkinsonism.  It was first noted in 1980 that some patients with GD also exhibit parkinsonism. Several other publications have since confirmed that patients with adult onset GD have up to a 20 fold higher chance of developing parkinsonism or diffuse Lewy body disease (DLBD). More recently in 2004, Sidransky and colleagues noted that patients with GD and parkinsonism frequently had relatives with parkinsonism that were heterozygous for GBA1 mutations.  Neuropathological analysis revealed the presence of Lewy bodies in the brains of these GD patients similar to those found in idiopathic PD or DLBD.   Additionally, genotyping studies using large patient cohorts have identified mutations in the GBA1 gene (that causes Gaucher) as one of the highest risk factor (genetic or environmental) for developing idiopathic PD to date.  Therefore, the clinical and genetic link between GD and parkinsonism has been established in “both directions”—patients with GD and their relatives have increased incidence of parkinsonism, and patients with idiopathic parkinsonism have increased incidence of mutations in the gene glucocerebrosidase (GC) that causes GD.

However, the molecular mechanism that would explain how this rare lysosomal storage disorder is linked to adult onset synucleinopathies and neurodegeneration has been largely unknown.  In our recent data, we provide evidence that establishes a link between glucosylceramide  metabolism and alpha-synuclein accumulation (Mazzulli et al, Cell, 2011). Using mouse and human iPS neuronal models, we found that loss-of-function mutations in glucocerebrosidase (GC) result in lysosomal dysfunction, accumulation of alpha-synuclein and neurodegeneration.

An unexpected finding occurred in the course of our studies on the GD-PD linkage: alpha-synuclein was identified as a modulator of GCase trafficking which partially prevents its movement into the lysosome. This suggested that accumulation of wt alpha-synuclein alone, an invariable characteristic of all synucleinopathies, can functionally mimic the effect of an established lysosomal enzyme mutation. These results suggested that alpha-synuclein and GC are directly connected in a pathogenic feedback loop leading to a self-propagating disease cycle (Figure 1).

We propose that therapeutic targeting of mutated or normal glucocerebrosidase to lysosomes is expected to prevent or diminish formation of toxic a-syn oligomers and break the vicious cycle of alpha-synuclein aggregation and toxicity.   We suggest that this pathway applies to any disease that is characterized by accumulation of a-synuclein including Parkinson’s disease.   Most importantly, this approach identifies a specific target, glucocerebrosidase, for therapeutic development in Parkinson’s Disease and neuronopathic Gaucher’s disease.

Dimitri Krainc M.D. PhD  … “Harvard Medical School”