Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alpha-synuclein (αsyn) aggregation is central to synucleinopathies such as Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB).
• Mechanisms governing αsyn propagation and aggregation remain incompletely understood.
• Previous work identified elevated Rab27b in PD/DLB and its role in αsyn clearance.

Purpose of the Study:

• To further characterize the role of Rab27b in neuronal lysosomal processing and αsyn clearance.
• To investigate the impact of Rab27b deficiency on lysosomal function and αsyn aggregation.
• To explore Rab27b as a potential therapeutic target for synucleinopathies.

Main Methods:

• Utilized an αsyn inducible neuronal model with Rab27b knockdown (KD).
• Examined primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice.
• Assessed lysosomal function, αsyn levels, aggregation, and acidic vesicle trafficking.
• Investigated Rab27b overexpression (OE) effects and analyzed human postmortem brain tissue.

Main Results:

• Rab27b KD led to lysosomal dysfunction and increased lysosomal αsyn.
• Rab27b KO neurons exhibited impaired lysosomal proteolysis and exacerbated αsyn aggregation.
• Defects in acidic vesicle trafficking were observed in Rab27b KO neurons.
• Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn.
• Elevated Rab27b levels were found in human incidental Lewy Body Disease (iLBD) subjects.

Conclusions:

• Rab27b plays a significant role in neuronal lysosomal activity and αsyn clearance.
• Dysfunctional Rab27b contributes to αsyn aggregation and pathology in synucleinopathies.
• Rab27b represents a potential therapeutic target for treating synucleinopathies.