Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions

Table 3 Targeting intercellular spread of ⍺-syn

Target	Mechanism	In vitro evidence	In vivo evidence	Intervention
Passive diffusion for extracellular release of α-syn	Releases α-syn into extracellular matrix	Yes	Yes	Targeting “naked” α-syn in extracellular matrix	[92, 93, 97]
Exocytosis/vesicular transport	Releases α-syn into extracellular matrix	Yes	Yes	Inhibiting exocytosis and vesicular transport	[98,99,100,101]
Tunneling nanotubes	Transports α-syn across extracellular matrix to recipient cells from donor cells	Yes	Yes	Disrupting formation of TNTs	[104,105,106,107]
Passive diffusion for cellular uptake of α-syn	Uptakes α-syn into recipient cells	Yes	Yes	Targeting “naked” α-syn in extracellular matrix or mutating sequence motifs on α-syn that modulates binding to plasma membrane	[110,111,112,113,114]
Endocytosis/exosomal uptake	Uptakes α-syn into recipient cells	Yes	Yes	Inhibiting endocytosis and exosomal uptake	[115,116,117]

Different methods in which α-syn can propagate from cell to cell and their respective intervening strategies.

ISSN: 1750-1326