Page 18 - Rappaport Institute Magazine 2024

BIOCHEMISTRY
Simone Engelender, MD, PhD Professor of Biochemistry
MD, 1993 – The Federal Univ. of Rio de Janeiro, Brazil PhD, 1996 – The Federal Univ. of Rio de Janeiro, Brazil
A novel peptide that prevents a-synuclein pathology in Parkinson’s disease models: a potential new therapy for Parkinson’s disease and other a-synucleinopathies
Parkinson’s disease (PD) is a common neurodegenerative disorder that affects millions of people worldwide and neuronal death are due to the accumulation and aggregation of a-synuclein. There is no treatment that can halt PD progression and clinical trials using antibodies against a-synuclein failed to improve the disease. Therefore, there is an urgent need to find agents that can treat PD and other a-synucleinopathies, such as dementia with Lewy bodies (DLB). We have previously found that monoubiquitinated a-synuclein is targeted for proteasomal degradation and that SUMOylation antagonizes monoubiquitination and leads to a-synuclein aggregation. As a targeted approach, we developed a cell-penetrating peptide that prevents a-synuclein SUMOylation and enhances its degradation. We found that this peptide significantly reduces the levels and pathology of a-synuclein in neurons and in mice. We believe SUMOylation of a-synuclein is an important target and that the peptide we developed may be a viable strategy to treat PD and other a-synucleinopathy patients.
Selected Publications
ˆ Rott, R., Szargel, R., Shani, V., Hamza, H., Savyon, M., Bandopadhyay,
R. and Engelender, S. SUMOylation and ubiquitination reciprocally regulate a-synuclein degradation and pathological aggregation. Proc. Natl. Acad. Sci. U.S.A., 14: 13176-13181, 2017.
Paper featured in Movement Disorders, Vol. 33, No. 3, 2018 (Hot Topics)
ˆ Engelender, S.* and Isacson, O.* The Threshold Theory for Parkinson’s disease. Trends Neurosci. 40: 4-14, 2017.
ˆ Abeywardana, T., Lin, Y.H., Rott, R., Engelender, S.* and Pratt MR.* Site- Specific differences in proteasome-dependent degradation of monoubiquitinated a-synuclein. Chem Biol. 20: 1207-1213, 2013.
ˆ Rott, R., Szargel, R., Haskin, Y., Bandopadhyay, R., Lees, A. J., Shani
V. and Engelender, S. a-Synuclein fate is determined by USP9X-regulated monoubiquitination. Proc. Natl. Acad. Sci. U.S.A. 108: 18666-71, 2011.
Grants and Awards
2014 – Research Award from Teva Pharmaceutical Industries (Nominated by the ISF), Israel
2022-2025 – Ministry of Health, Israel
2024-2025 – Short-term Translational Research Grant, Rappaport Institute 2024-2026 – University of Michigan-Israel Partnership for Research
2024-2027 – Technion-Einstein Partnership for Collaborative Research
simone@technion.ac.il
Simone Englender Lab
Localization of the BBB transporter Slc38a5 (magenta) in veins and capillaries of the BBB (green). This transporter mediates an essential influx of serine required for neurodevelopment. From Radzishevsky et al., 2023.