engleski

Retromer dysfunction in a rare neurodegenerative disorder Niemann-Pick type C

Retromer is a protein complex involved in the retrieval of endolysosomal proteins from endosomes to trans-Golgi network, as well as their recycling to the plasma membrane. Retromer dysfunction has been reported in the pathogenesis of the most common and complex neurodegenerative disorders, Alzheimer’s disease (AD) and Parkinson’s disease (PD), suggesting that normal retromer function is important for neuronal survival. In this work we tested whether altered function of retromer is involved in the pathogenesis of a rare childhood neurodegenerative disorder Niemann-Pick type C (NPC). Interestingly, recent studies have established several links between NPC and AD, indicating that the two disorders may share common pathological pathway(s). To test this, we used in vitro and in vivo models of NPC. Subcellular and regional distribution of retromer proteins Vps26, Vps35 and retromer receptor sorLA were analysed by immunocyto(histo)chemistry in: Chinese Hamster Ovary cells (CHOwt) and CHO NPC1-null cells ; hippocampi, cerebella and cortices of NPC1+/+ (wt) and NPC1-/- mice and in primary neurons from wt and NPC1-/- mice. Altered trafficking of retromer proteins was observed in NPC1-null vs. CHOwt cells. In NPC1-/- mouse brains we detected decreased sorLA immunostaining that was accompanied with Vps35 accumulation in neuronal soma at the early disease stage. In primary NPC1-/- neurons, retromer was sequestered in axons and accumulated in axonal swellings. Our studies indicate that retromer dysfunction could be involved in neurodegenerative processes in NPC disease. Thus, retromer could be an interesting target to develop treatments against this untreatable and devastating neurodegenerative disorder.

cholesterol ; endolysosomal trafficking ; neurodegeneration ; NPC1 ; retromer

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