Investigation of the effects of glucosylceramidase-beta gene mutations on α-synuclein degradation mechanisms in dopaminergic neurons

Mutations in Glucosylceramidase-beta (GBA) gene which is encoding the lysosomal Glucocerebrosidase (GCase) enzyme cause Gaucher's Disease (GD), an autosomal recessive inherited lysosomal storage disease. GD is characterized by the accumulation of lysosomal glucocerebroside in Gaucher cells and these cells cause disease pathology by affecting different tissues and systems such as liver, spleen, bone marrow, lung, and nervous system. Gaucher's disease is divided into clinical subtypes according to neurological findings: Type I (non-neuropathic form), Type II (acute neuropathic form) and Type III (chronic neuropathic form). Recently, it has been described that GBA mutations that have been proven to be associated with GD are the most important risk factors for Parkinson's Disease (PD) and other synucleopathies. Molecular analyses have shown that mutant Glucocerebrosidase (GCase) enzyme triggers the α-synuclein accumulation and cause PD pathology. Although several different mechanisms have been proposed to explain the pathological relationship between GCase and α-synuclein accumulation, such as intracellular lipid composition alteration, autophagic/lysosomal dysfunction, ubiquitin protease system degradation and intracellular calcium balance impairment, the basis of the relationship between the two diseases is still unclear. One of the pathological mechanisms proposed to explain the pathological relationship between GD and PD is that GBA mutations result in intracellular α-synuclein accumulation by affecting protein degradation mechanisms. Studies have shown that GCase enzyme deficiency may cause α-synuclein accumulation by affecting the ubiquitin-proteasome system (UPS), chaperone-mediated autophagy (CMA), and macroautophagy mechanisms which are responsible for the degradation of α-synuclein. These mechanisms may compensate each other to maintain protein quality control system in the cell. However, it is not known exactly how the lack of GCase enzyme affects these mechanisms. In the light of these, it has been hypothesized that different GBA mutations that cause neuropathic and non-neuropathic Gaucher's Disease may play role in neuronal degeneration process by affecting -degradation mechanisms of α-synuclein in the cell. For this purpose, we are planning to investigate the effects of GBA mutations on α-synuclein degradation mechanisms, namely Ubiquitin-Proteasome System (UPS), Chaperone-mediated Autophagy (UPS), in induced pluripotent stem cell (iPSC) derived dopaminergic neuron cultures obtained from fibroblasts of Gaucher patients with different neurological involvement and Parkinson's patients. Determination of the effects of GBA mutations on α-synuclein degradation mechanisms is of great importance for clarifying the pathogenesis of the neurologically involved Gaucher's disease.