Excess α-synuclein compromises phagocytosis in iPSC-derived macrophages

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Parkinson's Disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αS) aggregation.
• Understanding the role of αS in PD pathogenesis is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the pathogenic role of αS in Parkinson's Disease using patient-derived induced pluripotent stem cell lines.
• To assess the function of PSC-macrophages (pMac) in clearing αS and their response to different αS mutations.

Main Methods:

• Generated induced pluripotent stem cell lines from early-onset PD patients with SNCA A53T and SNCA Triplication mutations.
• Differentiated these cell lines into PSC-macrophages (pMac).
• Assessed intracellular and extracellular αS levels, phagocytosis capability, αS uptake pathways, and degradation mechanisms in pMac.

Main Results:

• SNCA Triplication pMac exhibited significantly increased intracellular αS and higher αS release compared to controls.
• SNCA Triplication pMac showed significantly reduced phagocytosis capability, which could be replicated by adding monomeric αS to control pMac.
• Fibrillar αS uptake occurred via actin-rearrangement-dependent pathways, while monomeric αS was taken up via actin-independent pathways.
• pMac demonstrated the ability to degrade αS, a process inhibited by blocking lysosomal and proteasomal pathways.

Conclusions:

• Macrophages are capable of clearing αS.
• Elevated levels of αS, whether endogenous or exogenous, compromise the clearance ability of pMac.
• This impaired clearance may contribute to a vicious cycle in Parkinson's Disease pathogenesis, particularly affecting microglia.