Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.
Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Lausanne, CH · Author affiliation
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.Location evidence
Palo Alto, US · Author affiliation
Stanford Medicine, Department of Neurology and Neurological Sciences, Palo Alto, CA, USA.Location evidence
Oxford, GB · Author affiliation
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.Location evidence
London, GB · Author affiliation
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.Location evidence
Lund, SE · Author affiliation
Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.Location evidence
Shenyang, CN · Author affiliation
Institute of Health Sciences, China Medical University, Shenyang, China.Location evidence
Braine-l'Alleud, BE · Author affiliation
UCB Biopharma SPRL, Braine-l'Alleud, Belgium.Location evidence
Doha, QA · Author affiliation
Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar. hilal.lashuel@epfl.ch.Location evidence
New York City, US · Author affiliation
Department of Neurology, Weill Cornell Medicine, New York, NY, USA. hilal.lashuel@epfl.ch.Location evidence
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Original abstract
Alpha-synuclein (aSyn) post-translational modifications (PTM), especially phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LB), Lewy neurites, and other pathological aggregates in Parkinson's disease and synucleinopathies. However, the precise role of these PTM in pathology formation, neurodegeneration, and pathology spreading remains unclear. Here, we systematically investigated the role of post-fibrillization C-terminal aSyn truncations in regulating uptake, processing, seeding, and LB-like inclusion formation using a neuronal seeding model that recapitulates LB formation and neurodegeneration. We show that C-terminal cleavage of aSyn fibrils occurs rapidly post exogenous fibril internalization and during intracellular LB-like inclusion formation. Blocking cleavage of internalized fibrils does not affect seeding, but inhibiting enzymes such as calpains 1 and 2 alters LB-like inclusion formation. We show that C-terminal truncations, along with other PTMs, regulate fibril interactome remodeling, shortening, lateral association, and packing. These findings reveal distinct roles of C-terminal truncations at different aggregation stages on the pathway to LB formation, highlighting the need for consideration of stage‑specific strategies to target aSyn proteolytic cleavages.