SUMMARY

In 2014, we have shown that α-synuclein species contained in nigral Lewy bodies (LB) from postmortem brains of patients with Parkinson’s disease (PD) have the capacity to trigger a PD-like pathological process when directly injected into the brain of mice and monkeys, including intracellular and pre-synaptic accumulations of pathological α-synuclein in different interconnected brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration. These pathogenic effects (i) required both human α-synuclein present in LB extracts and host expression of α-synuclein, and (ii) were not observed in animals inoculated with non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. On the other hand, we have shown that the pro-apoptotic protein Bax, which is known to permeabilize mitochondrial membranes in PD models and is activated in PD patients, is also able to permeabilize lysosomal membranes in animal models of PD, resulting in the lysosomal-autophagic defects that occurr in this disease. Furthermore, pharmacological inhibition of Bax-induced permeabilization, in both mitochondria and lysosomes, was shown to attenuate PD-linked dopaminergic neurodegeneration in experimental PD models. These results indicate that PD-related lysosomal impairment relies on Bax-induced lysosomal membrane permeabilization and point to small molecules able to block Bax channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.

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