Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms

Area of Science:

• Neurodegenerative diseases
• Lysosomal biology
• Parkinson disease pathogenesis

Background:

• Lysosomal dysfunction is increasingly linked to neurodegenerative diseases, particularly Parkinson disease (PD).
• Alpha-synuclein (aSyn) aggregation in Lewy bodies is a key pathological feature of PD.
• Mutations in lysosomal enzymes are identified risk factors for PD.

Purpose of the Study:

• To review the complex role of lysosomes in the pathogenesis of Parkinson disease.
• To explore the interplay between alpha-synuclein proteoforms and lysosomal function.
• To evaluate the therapeutic potential of modulating lysosomal function in PD.

Main Methods:

• Review of existing scientific literature on lysosomal function and alpha-synuclein in Parkinson disease.
• Analysis of the impact of alpha-synuclein posttranslational modifications and aggregation on lysosomal degradation.
• Examination of how lysosomal enzymatic activity influences alpha-synuclein proteoform generation.

Main Results:

• Diverse alpha-synuclein proteoforms interfere with lysosome function, hindering their own degradation and promoting aggregation.
• Dysfunctional lysosomal processes can generate toxic, aggregation-prone truncated alpha-synuclein species.
• The relationship between alpha-synuclein and lysosomes is bidirectional and complex, not a simple degradation pathway.

Conclusions:

• Targeting lysosomal function for PD treatment is promising but requires careful evaluation to avoid generating harmful alpha-synuclein variants.
• Further research is needed to confirm if enhancing lysosomal activity can safely reduce toxic alpha-synuclein proteoforms.
• Understanding the intricate interactions between alpha-synuclein and the lysosome is crucial for developing effective PD therapies.