The Lysosome: Hub for α-Synuclein Aggregation and Degradation?


Event details

Date 23.11.2023
Hour 10:0011:00
Speaker Prof. Friederike Zunke, Group Leader, Department of Molecular Neurology, University Hospital Erlangen / FAU Erlangen-Nürnberg (Germany)
Location Online
Category Conferences - Seminars
Event Language English
Synucleinopathies are neurodegenerative disorders characterized by the abnormal intracellular accumulation of α-synuclein (aSyn), including Parkinson’s disease (PD) as well as Multiple System Atrophy (MSA). While the exact mechanisms underlying aSyn pathology have not been fully understood, increasing evidence suggests the involvement of autophagic as well as lysosomal pathways to disease pathology, especially for PD. Our studies focus on the effect of aSyn aggregates on lysosomal function and turnover, particularly focusing on lysosomal transport and homeostasis.  Since lysosomal enzymes comprising cathepsins have been shown to be directly involved in the lysosomal degradation of aSyn, impairment of their enzymatic capacity has extensive consequences.
Further, we propose the lysosome and its enzymes (in particular cathepsins) as therapeutic target for synucleinopathies. Hence, strategies to increase lysosomal trafficking and direct application of aSyn-degrading lysosomal enzymes (cathepsins) are tested to evaluate the effects on aSyn pathology and neuronal function.
In our studies, we apply state-of-the-art technology of induced pluripotent stem cells (iPSC) of PD patients and mouse models harboring aSyn pathology. aSyn conformers and their effects on cellular homeostasis and lysosomal function was evaluated by biochemical analyses as well as intracellular lysosomal live-cell assays.
In patient-derived dopaminergic neurons and a mouse model harboring aSyn aggregation, we show that lysosomal trafficking of cathepsins as well as b-glucocerebrosidase (one of the highest genetic risk factors to develop PD) is impaired, resulting in reduced proteolytic activity of these enzymes in the lysosome. Our studies show that boosting lysosomal function, e.g. vis the administration of recombinant human proforms of cathepsins (CTSD and CTSB) results in a decrease of pathology-associated aSyn and restores neuronal function.
Altogether, our findings demonstrate a strong interplay between aSyn aggregation pathways and function of lysosomal enzymes. It appears that aSyn interferes with the enzymatic function of cathepsins leading to a vicious cycle of impaired aSyn degradation.

Professor Friederike Zunke obtained a Bachelor’s degree in biochemistry at the University of Kiel (Kiel, Germany) and a Master’s degree in biomedical sciences at the St. George’s University (London, UK). She received a PhD from the biochemical department at the University of Kiel in 2015 for work focused on intracellular mechanisms and the role of lysosomal dysfunction in neurodegeneration. She continued to work on lysosomal pathways and alpha-synuclein aggregation processes during her postdoctoral training in the department of neurology of the Northwestern University in Chicago. In 2016, she began work as an independent group leader in the Institute of Biochemistry at the University of Kiel (Germany), and in 2020 she was appointed as junior professor for translational neurosciences in the department of molecular Neurology at the University Hospital Erlangen, where she and her group continue to work on molecular and structural mechanisms of Parkinson’s disease.

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