Parkinsonisms associated with Gaucher disease: glucocerebrosidase for alpha-synuclein clearance

Project information

The role of mutations in the GBA1 gene coding for the enzyme beta-glucocerebrosidase (GCase) in the development of Parkinson's disease (PD) and other synucleinopathies such as dementia with Lewy bodies (DLB) has been described very recently.

Studies in patients with Gaucher disease (a lysosomal storage pathology due to GBA1 mutations) have revealed that these mutations are the most common risk factor for PD and DLB. Individuals carrying GBA1 mutations develop PD somewhat earlier than non-carriers (about 5 years earlier) and more frequently present with cognitive impairment and neuropsychiatric symptoms.

The association between GBA1 mutations and DLB is even more striking. Although the exact mechanism through which GCase regulates alpha-synuclein (SYN) homeostasis is not yet fully understood, the reduction of GCase activity as a promoter of the neuropathological findings typical of these synucleinopathies is well documented and has led to the development of different novel strategies aimed at increasing GCase activity to produce SYN clearance and arrest dopaminergic cell death.

In this research project we will proceed to use an adeno-associated viral vector that we have recently developed to overexpress mutated SYN in neurons of the substantia nigra of non-human primates (NHPs) Macaca fascicularis. Next, we will employ another adenoassociated viral vector to provide dopaminergic neurons with the GBA1 gene to induce SYN clearance. Similar experiments will be carried out with viral vectors to overexpress mutated Tau in the Meynert basal nucleus of NHPs, followed by their potential clearance with the GBA1 vector.

To date there is very limited experimental evidence on how SYN degradation, aggregation and subcellular processing are related to GCase activity, and vice versa. Therefore, and in parallel to the studies in NHPs, we will proceed to perform a complete proteomic study in human brain samples from patients with advanced of human brains from patients in advanced stages of PD and in control subjects in order to identify new biological targets at the interface between GCase and SYN. These studies will be carried out in the substantia nigra pars compacta, nucleus basalis of Meynert and locus ceruleus, as these are brain areas where pathology derived from the accumulation of misfolded proteins such as SYN and tau is usually observed.

Preliminary studies carried out in our laboratory show that it is precisely the neurons of these specific brain areas that have a higher basal GCase activity, much higher than any other territory. The existence of a very evident genetic association between GBA1 mutations and synucleinopathies such as PD and DLB supports the consideration of GCase as an interesting target for the treatment of these diseases. In fact, preliminary data that we have recently obtained suggest that GCase would be involved in different types of neurodegenerative proteinopathies and not only in synucleinopathies.

It is hoped that new data and innovative ideas can be obtained from the experimentation proposed here to elucidate the role of GCase in the homeostasis of SYN and other proteinopathies such as tau.

It is 50% co-funded by the European Regional Development Fund through the 2014-2020 ERDF Operational Program of Navarra. European Union. European Regional Development Fund. A way of doing Europe.

• Convocation: Proyectos de Investigación en Ciencias de la Salud 2017. Gobierno de Navarra Dtpo. Salud
• Reference: 46/2017
• Duration: 3 años
• Start date: December 15, 2017
• End date: December 14, 2020
• Funder: Comisión Europea
• Grant: 74.106,01 €
• Nature of project: European