Wednesday, January 15, 2025
1/15/2025
Recent evidence points to αsyn misfolding and cell-to-cell transmission as critical to neurodegeneration in Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). Key steps implicated in αsyn spread include release, uptake, misfolding, and impaired protein degradation, yet the key molecular mechanisms that regulate αsyn spread are poorly understood. Rab proteins are small GTPase proteins that control protein trafficking and degradation and have been implicated in αsyn pathogenesis. Among the Rab proteins, Rab27b is highly expressed at synaptic terminals in neurons in key brain areas affected in PD and DLB. Rab27b regulates synaptic vesicle (SV) exocytosis and recycling. In non-neuronal cells, Rab27b regulates the distal transport of lysosomes. We recently showed elevated Rab27b levels in αsyn models and in human PD and DLB. Furthermore, we observed that Rab27b KD increases αsyn toxicity by disrupting autophagic flux - pointing to a protective role for Rab27b in cells with high intracellular αsyn burden. Surprisingly, the effects of Rab27b were different in the αsyn fibril model, in which neurons were exposed to extracellular αsyn fibrils: Rab27 KO reduced fibrillary αsyn uptake to prevent αsyn inclusions and neuronal loss. Based on these data, we hypothesize that Rab27b plays two critical yet potentially opposing roles in αsyn handling: 1) Rab27b promotes αsyn autophagic-lysosomal degradation, yet 2) Rab27b can facilitate endocytosis of pathologic, extracellular αsyn as part of its role in SV recycling. Early in disease, we propose that Rab27b upregulation is neuroprotective: Rab27b aids intracellular αsyn clearance. Yet, as disease progresses and extracellular αsyn levels increase, Rab27b’s role in SV endocytosis becomes maladaptive, overcoming any protective function in protein degradation, and aids αsyn cell-to-cell transmission. Our proposed studies will examine the impact of Rab27b and its interactors on two critical biological processes implicated in αsyn pathogenesis. In Aim 1, we will test the mechanisms by which Rab27b promotes clearance of intracellular αsyn, and examine its interactions with other proteins involved in autophagic-lysosomal function. In Aim 2, we will elucidate the mechanisms by which Rab27b aids αsyn entry into neurons and determine its interaction with other synaptic trafficking proteins to mediate this effect. In Aim 3, we will test the overall consequences of Rab27b on αsyn pathology over time in two in vivo αsyn models. A greater understanding of the network of proteins that shape αsyn transmission will have significant impact on the development of future therapies for PD and DLB.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).