Neuronal aggregation of the protein alpha-synuclein (αS) in Lewy bodies is a hallmark of key Alzheimer Disease and Related Disorders (ADRDs) including Lewy Body Dementia (LBD), Parkinson’s disease with dementia (PDD) and mixed AD/LB dementia. Collectively these disorders affect millions of US citizens. Understanding mechanisms of αS toxicity thus holds key import for understanding and treating ADRD. αS reversibly associates with cellular membranes in neurons and this interaction is clearly important for toxicity, but the underlying mechanisms remain unclear. Moreover, αS is also highly abundant in the cytosol. What αS is doing in different cellular compartments and how this may be relevant to neurotoxicity when αS abnormally accumulates in ADRD remains unknown. Our previous extensive genetic and physical αS interaction mapping connected αS not only to membrane trafficking proteins but also to a surprising number of RNA-binding proteins (RBPs). However, while RBP dysregulation and loss of RNA homeostasis are clearly important contributors to neurodegeneration in general, a direct link between αS and RBPs was elusive until now. We recently found that αS can perturb RNA homeostasis by directly interacting with and disrupting the mRNA decapping machinery found in Processing Bodies, membraneless ribonucleoprotein complexes responsible for mRNA turnover. αS strongly interacts with decapping proteins of P-bodies in neurons. Importantly, the exact same (N-terminus) αS region is responsible for binding to membranes and to P-body proteins. This sets up a dichotomous relationship whereby alterations at the membrane can directly affect gene regulation through redistributing αS between membrane and cytosolic compartments. On the basis of our findings in human iPSC neurons and postmortem brain, we hypothesize that αS shuttles between membranes and P-bodies and, upon accumulation to toxic levels, disrupts P- body composition and mRNA turnover. Model organism and human genetics analyses also support a causal influence of the P-body pathway in modulating αS toxicity an PD risk. Here, we will, first, rigorously test these connections by measuring P-body perturbations in a wide-range of synucleinopathy models, postmortem brain and mouse models and assess the direct impact of P-body genes on neurotoxicity. Second, we will investigate which specific mRNA transcripts and subclasses of mRNAs are impacted by αS accumulation or mutation. Finally, we will investigate how αS modulates decapping enzymology and composition in a fully in vitro reconstituted system. We anticipate that this study will reveal that RNA homeostasis disruption is a key aspect of Lewy body disease pathogenesis and motivate new treatment strategies for ADRD.

The neuronal aggregation of alpha-synuclein is deeply connected to Parkinson’s Disease and Alzheimer’s Disease Related Dementias. We recently uncovered an entirely new mechanism of alpha-synuclein toxicity in neurons, through modulation of mRNA. We will now systematically assess how important this is across a range of neuronal models and postmortem brain samples, examine why certain mRNAs are more perturbed in synucleinopathy, and determine key enzymes in the pathway that may be prospective therapeutic targets.