DOPAL oligomerizes alpha-synuclein in glial cells. Implications for the pathogenesis of multiple system atrophy

      Background: Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein (AS) characterize multiple system atrophy (MSA). Sources of AS in GCIs are poorly understood. Glial cells can take up AS from the extracellular fluid. 3,4-Dihydroxyphenylacetaldehyde (DOPAL), a toxic intermediate metabolite of dopamine, oligomerizes AS, and oligomerized AS is thought to be the pathogenic form of the protein. We reported previously that endogenous DOPAL produced in catecholaminergic PC12 cells can be taken up by co-incubated human glioblastoma cells; however, whether DOPAL oligomerizes AS in glial cells has been unknown. Aim: In this study we tested whether DOPAL taken up by glial cells augments AS oligomerization. Methods: DOPAL and AS (native or A53T mutant) were added to the incubation medium of glial cells. Cell contents of DOPAL and its intracellular metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) were measured at up to 3 hours of incubation. Cellular AS oligomers were quantified by Western blotting. Results: Glial cells did not contain endogenous catechols except for trace amounts of DOPA, and they contained no endogenous AS. Co-incubation of glial cells with PC12 cells resulted in time-related increases glial DOPAL content. Addition of DOPAL to the medium rapidly increased glial cell contents of DOPAL, DOPAC, and DOPET. Incubation of glial cells with native or A53T AS resulted in accumulation of these proteins in the cells, including oligomers. DOPAL enhanced the intracellular oligomerization of both native and A53T AS. Conclusions: DOPAL is transmissible to glial cells and enhances intracellular oligomerization of AS. An interaction of DOPAL with AS might help explain the formation of GCIs in MSA.
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