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Updated: Jan 10, 2026
09:16
Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
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Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution
Andrew Sam1, Seungwoo Lee1, Jordan Elliott1
1Department of Chemistry & Chemical Biology, Rutgers University, 123 Bevier Road, Piscataway, NJ 08854, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Protein aggregation, a hallmark of neurodegenerative diseases like Parkinson's, evolved over time. Ancestral sequence reconstruction reveals that fibril formation in alpha-synuclein (αSyn) is an acquired trait, not ancestral.
Area of Science:
- Evolutionary biology
- Neuroscience
- Biochemistry
Background:
- Protein aggregation, particularly of alpha-synuclein (αSyn), is central to neurodegenerative diseases like Parkinson's disease.
- The evolutionary origins and sequence determinants of αSyn aggregation remain largely unknown.
- Understanding these factors is crucial for developing therapeutic strategies targeting αSyn fibril formation.
Purpose of the Study:
- To investigate the evolutionary emergence of fibril-forming ability within the synuclein protein family.
- To identify the specific sequence changes that led to the aggregation propensity of αSyn.
- To elucidate the relationship between sequence evolution, conformational changes, and fibril formation.
Main Methods:
- Ancestral sequence reconstruction (ASR) to infer and resurrect ancestral synuclein proteins.
- Phylogenetic analysis to establish the evolutionary relationships within the synuclein family.
- Biophysical techniques including mass spectrometry and NMR to characterize protein structure and aggregation.
Main Results:
- ROOT synuclein, the common ancestor of all synucleins, is non-aggregating, indicating aggregation is an evolved trait.
- Fibril formation emerged at the ancestral αβ node and is present in αSyn but suppressed in β-synuclein.
- Evolutionary sequence changes progressively increased monomer conformational complexity, favoring fibril formation.
- Specific residue acquisitions stabilized the β-arch core and enhanced protofilament interactions, driving αSyn aggregation.
Conclusions:
- ASR provides a framework for understanding the evolution of synuclein aggregation.
- The transition from non-aggregating to aggregating forms involved stepwise sequence modifications.
- Evolutionary pressures remodeled synuclein monomers, leading to the molecular basis of αSyn fibril formation and associated diseases.
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