MitSyn · Alpha-synuclein and mitochondrial dysfunction: key links between Gaucher’s disease and Parkinson’s?
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-04-13 → 2017-04-12
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Alpha-synuclein and mitochondrial dysfunction: key links between Gaucher’s disease and Parkinson’s?
Mutations of a lysosomal enzyme termed glucocerebrosidase (GCase, encoded by the gene GBA) cause Gaucher’s disease (GD) but also have a strong association with Parkinson’s disease (PD). This enzyme is responsible for the recycling of a special class of lipids called glucosylcermides, which are cleaved into glucose and ceramides molecules inside the lysosomes. We have previously shown that GCase knockout in mice causes defects in the autophagy lysosomal pathway, which is responsible in cells to remove harmful macromolecules and dysfunctional organelles and recycle their primary components. These defects lead to profound mitochondrial dysfunction and accumulation of a protein termed alpha-synuclein (aS), a hallmark of PD. The mechanisms that drive impaired mitochondrial dysfunction in association with impaired activity of a lysosomal enzyme remain obscure. Thus, the basic objectives of the MitSyn project are i) to explore the mechanisms that associate mutations or deficiencies in GCase with mitochondrial dysfunction and aS accumulation, and ii) to explore the consequences of lysosomal and mitochondrial dysfunction on cell signaling pathways. To this end, we have used: i) primary neuronal and astrocytic cultures from mice in which GCase was knocked out, a model for the neuropathic form of the lysosomal storage disorder GD and ii) iPSC-derived neurons from patients with PD carrying mutations of the GBA gene. In these models, we characterized impairment of autophagy and lysosomal defects, mitochondrial dysfunction and impaired calcium homeostasis. Moreover, we modulated aS levels to study its role in mitochondrial damage. The Mitsyn project allowed to further characterize the interplay between lysosomes and mitochondria, which seems to be crucial in the aethiopathogenesis of several neurodegenerative disorders.
Data: CORDIS, © European Union
Project objective
Recent studies have highlighted a strong genetic association between Parkinson’s disease (PD) and Gaucher’s disease (GD), a lysosomal storage disorder that causes severe neurodegeneration in children and shares some pathophysiological features of PD. GD results from mutations that reduce activity of the enzyme glucocerebrosidase (GCase), causing impaired lysosomal function. It was recently shown that GCase mutations cause several defects associated with impaired cellular quality control - impaired autophagy, mitochondrial dysfunction and accumulation of oligomeric alpha-synuclein, a protein strongly involved in sporadic and genetic PD forms. In fact, alpha-synuclein aggregates are the main constituent of Lewy Bodies, characteristic proteins inclusions found in parkinsonian brains. While PD shows similar features and involves defects in the same pathways, it remains unclear how these diverse findings relate to each other.In the present study we propose to identify the specific interactions between intracellular signaling pathways, cellular quality control pathways and alpha-synuclein oligomerization in an attempt to generate a unifying hypothesis that brings together known features of GD and PD pathophysiology. We will use primary neuronal cultures from gba knockout mice and inducible pluripotent stem cells derived from the GD mouse model and from patients, in which alpha-synuclein will be overexpressed or silenced. Mitochondrial (dys)function, impaired clearance mechanisms and alpha-synuclein oligomerization will be quantitatively characterized in these models by means of an array of biochemical, biophysical and advanced imaging techniques. The results of the work will give us further insights into PD molecular mechanisms and may provide new therapeutic targets.
Original text from CORDIS.
Participants
- UNIVERSITY COLLEGE LONDON · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union