Abstract
Alpha-Synuclein (aSyn) misfolding and aggregation is common in several neurodegenerative diseases, including Parkinson’s disease and dementia with Lewy bodies, which are known as synucleinopathies. Accumulating evidence suggests that secretion and cell-to-cell trafficking of pathological forms of aSyn may explain the typical patterns of disease progression. However, the molecular mechanisms controlling aSyn aggregation and spreading of pathology are still elusive. In order to obtain unbiased information about the molecular regulators of aSyn oligomerization, we performed a microscopy-based large-scale RNAi screen in living cells. Interestingly, we identified nine Rab GTPase and kinase genes that modulated aSyn aggregation, toxicity and levels. From those, Rab8b, Rab11a, Rab13 and Slp5 were able to promote the clearance of aSyn inclusions and rescue aSyn induced toxicity. Furthermore, we found that endocytic recycling and secretion of aSyn was enhanced upon Rab11a and Rab13 expression in cells accumulating aSyn inclusions. Overall, our study resulted in the identification of new molecular players involved in the aggregation, toxicity, and secretion of aSyn, opening novel avenues for our understanding of the molecular basis of synucleinopathies.
Highlights
Aggregation of alpha-Synuclein is associated with a group of disorders known as synucleinopathies, that include Parkinson’s Disease (PD), Dementia with Lewy Bodies and Multiple System Atrophy [1,2,3]
In order to understand the contribution of different cellular pathways towards aSyn aggregation, we conducted an unbiased lentiviral vector-based RNA interference (RNAi) screen in a cellular model of aSyn oligomerization, based upon a bimolecular fluorescence complementation (BiFC) assay that we have previously described [18]
We identified four genes encoding Rab proteins (RAB8B, RAB11A, RAB13 and RAB39B) and five genes encoding kinases or signal transduction proteins (CAMK1, DYRK2, CC2D1A, CLK4 and SYTL5) that modulated aSyn oligomerization (Fig 1B and 1D and S1A Fig)
Summary
Aggregation of alpha-Synuclein (aSyn) is associated with a group of disorders known as synucleinopathies, that include Parkinson’s Disease (PD), Dementia with Lewy Bodies and Multiple System Atrophy [1,2,3]. The common pathological hallmark among these disorders is the accumulation of aSyn in aggregates within neurons, nerve fibers or glial cells [4,5]. It is widely established that aSyn can enter an amyloid pathway of aggregation, first as soluble, oligomeric species that, can accumulate in insoluble aggregates [22]. The role of the large protein inclusions, such as Lewy bodies (LBs), is unclear, but they may constitute a protective mechanism in neurons to neutralize and preclude the effects of more toxic aSyn intermediates [18,23,24,25]
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