Tri sélectif et recyclage

Wnt/β-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson’s Disease

“…However, the vast majority of PD cases are genetically complex, being the result of the combined action of common genetic variants in concert with environmental factors (see Section 3) [3,4,5,6,7,8,9]. Importantly, these gene products and their disease-associated mutations were shown to regulate several cellular pathways, including mitochondrial turnover, synaptic vesicle exocytosis/endocytosis, endosomal sorting, autophagy, and lysosomal functions that play vital roles in mDAergic neuron homeostasis [9,66,67,68,69,70,116,117,118,119,120,121,122,123,124,125]. In particular, Wnt signaling components appear to cross-talk with the majority of these critical pathways, thereby contributing to main cellular dysfunctions, as described.…”

“…VPS35, codified by PARK17 gene [117], is an essential subunit of the retromer complex. The VPS35 protein functions as a core subunit of a heteropentameric complex referred to as the retromer, and recent studies identified Wntless (Wls) and the retromer complex as essential components involved in Wnt signaling [118,119]. Emerging evidence indicates that the dominant mutation may act via both a toxic gain-of-function or a dominant-negative mechanism, or possibly via a potential combination of these mechanisms, and that VPS35 KO mice can also develop PD-like pathology [117].…”

“…Importantly enough, the earlier identification of Wntless, a sorting receptor for Wnt, and of the retromer, a protein complex required for the recycling of Wntless from endosomes to the trans-Golgi network [118,119], support a critical role for Wnt-dependent functions in “vesicle trafficking, recycling, and turnover, that may be central to the pathophysiology of PD” [118], with VPS35 mutations being potentially involved in dysregulation of Wnt secretion.…”