Objective: The purpose of this study is to investigate the effect of induction of exosomal a-syn secretion on PARK9-mediated neurotoxicity.

Background: Kufor-Rakeb syndrome (KRS) is a rare hereditary neurodegenerative disorder in which patients show parkinsonism with other neurological manifestations. KSR is caused by loss of function mutations in ATP13A2 (PARK9) which codes lysosomal type 5 P-type ATPase. Loss of PARK9 leads to lysosomal dysfunction, subsequent α-synuclein (α-syn) accumulation and abnormal mitochondrial respiration. We and others have shown that PARK9 deficiency also impaired secretion of exosomes and a-syn.

Methods: We used H4 cells and midbrain DA neurons differentiated from patient-derived iPS cells. First, we silenced the expression of ESCRTIII-associated protein ALIX, which is known to play an important role in multivesicular body (MVB) formation. We also tried neutral sphingomyelinase (n-SMase), which is known to induce exosome secretion in the ESCRT machinery independent manner. We then conducted a series of experiments including exosome measurement, a-syn immunoblotting and mitochondria respiration.

Results: Both ALIX silencing and n-SMase treatment were able to increase the number of exosomes. While ALIX silencing lead to decreased a-syn levels through exosomal a-syn secretion, n-SMase treatment failed to attenuate a-syn accumulation in KRS DA neurons. While both did not affect lysosomal proteolysis, ALIX silencing improved mitochondria respiration.

Conclusions: These results demonstrate that α-syn is secreted by exosomes that are produced through ESCRT-dependent MVB biogenesis. Enhancing this pathway can reduce intracellular α-syn levels. These results highlight the importance of exosomal secretion to reduce intracellular protein levels and normal cellular functions. Therefore, targeting exosomes offers potential therapeutic opportunities not only for KRS, but also diseases characterized by the accumulation of pathological proteins.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/exosomal-alpha-synuclein-secretion-is-beneficial-for-cellular-models-of-kufor-rakeb-syndrome/