Alpha-Synuclein Interactions in Neurodegenerative Disorders

Alpha-synuclein is a small presynaptic protein that, under normal conditions, exists largely in a disordered conformation and participates in synaptic vesicle trafficking and neurotransmitter release. In a range of neurodegenerative disorders known collectively as synucleinopathies—most notably Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy—alpha-synuclein undergoes misfolding, oligomerisation and fibril formation. These aberrant species interact with diverse cellular partners, including cytoskeletal regulators, chaperones and elements of the autophagy-lysosome system. Pathogenic protein–protein interactions drive the seeding and cell-to-cell propagation of toxic aggregates, impair degradation pathways and disrupt neuronal and glial homeostasis. Understanding the molecular interfaces and dynamic assemblies that underpin both physiological functions and pathological cascades has opened avenues for interventions that aim to stabilise native structures, prevent harmful complexes or enhance clearance mechanisms, thereby offering hope for disease-modifying therapies across synucleinopathies.

Research from Nature Portfolio

Recent studies have revealed how tubulin polymerisation-promoting protein (TPPP/p25) utilises two intrinsically disordered binding sites to cooperate in microtubule bundling, a process that underpins the formation of pathological inclusions in neurodegenerative disease. Detailed deletion analyses demonstrated that, once bound to microtubules, the central folded domain of TPPP/p25 drives homotypic protein–protein interactions, reinforcing filamentous assemblies that can co-aggregate with alpha-synuclein in neurons and oligodendrocytes. This work pinpoints discrete structural elements responsible for both physiological cytoskeletal organisation and pathological aggregate formation, offering targeted regions for the design of molecules capable of disrupting deleterious complexes without compromising normal microtubule dynamics.

Alpha-Synuclein Interactions in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in alpha-synuclein interactions in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Alpha-synuclein: A presynaptic intrinsically disordered protein prone to misfolding and aggregation in synucleinopathies.

TPPP/p25: Tubulin polymerisation-promoting protein, an intrinsically disordered regulator of microtubules that co-aggregates with alpha-synuclein.

Intrinsically disordered protein (IDP): A protein lacking fixed tertiary structure under physiological conditions, often engaging in multiple interactions.

Synucleinopathy: A neurodegenerative disorder characterised by pathological aggregation of alpha-synuclein, including Parkinson’s disease.

Protein–protein interaction (PPI): The specific physical contact between protein molecules that governs cellular assemblies and signalling.

Oligomerisation: The assembly of a few monomeric proteins into a structured complex, frequently a step towards fibril formation in disease.

References

1. Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP. Cells (2024).
2. The Sherpa hypothesis: Phenotype-Preserving Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes. npj Systems Biology and Applications (2023).
3. Alpha-synuclein: from secretion to dysfunction and death. Cell Death & Disease (2012).
4. Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins. International Journal of Molecular Sciences (2022).
5. The Interplay between Alpha-Synuclein Clearance and Spreading. Biomolecules (2015).
6. Self protein-protein interactions are involved in TPPP/p25 mediated microtubule bundling. Scientific Reports (2015).