Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation

Area of Science:

• Neurobiology
• Neurodegenerative Diseases
• Cell Biology

Background:

• Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and myelin disruption.
• The precise mechanisms driving αSyn accumulation in MSA remain elusive, hindering therapeutic development.

Purpose of the Study:

• To investigate the role of epsin-2 in the propagation of αSyn aggregates in MSA.
• To identify potential therapeutic targets for mitigating αSyn pathology in MSA.

Main Methods:

• Utilized mouse models of MSA (PLP-hαSyn and FABP7/αSyn hetero-aggregate injected mice).
• Performed bioinformatic analyses on whole blood from MSA patients and FABP7 knockdown mice.
• Employed adeno-associated virus type 5 (AAV5)-mediated knockdown of epsin-2 in mice.

Main Results:

• Fatty acid-binding protein 7 (FABP7) forms toxic hetero-aggregates with αSyn, selectively accumulating in oligodendrocytes and Purkinje neurons, leading to cerebellar dysfunction.
• Bioinformatic analysis identified epsin-2 as a potential regulator of FABP7/αSyn hetero-aggregate propagation via clathrin-dependent endocytosis.
• Knockdown of epsin-2 reduced αSyn aggregate levels, improved myelin integrity, and enhanced Purkinje neuron function and motor performance in the cerebellum.

Conclusions:

• Epsin-2 significantly contributes to αSyn accumulation in MSA by mediating the propagation of toxic FABP7/αSyn hetero-aggregates.
• Epsin-2 emerges as a promising novel therapeutic target for MSA treatment.