Endosomal Dysfunction in iPSC-Derived Neural Cells from Parkinson’s Disease Patients with VPS35 D620N

Abstract

Mutations in the Vacuolar protein sorting 35 (VPS35) gene have been linked to familial Parkinson’s disease (PD), PARK17. VPS35 is a key component of the retromer complex, which plays a central role in endosomal trafficking. However, whether and how VPS35 deficiency or mutation contributes to PD pathogenesis remain unclear. Here, we analyzed human induced pluripotent stem cell (iPSC)-derived neurons from PD patients with the VPS35 D620N mutation and addressed relevant disease mechanisms. In the disease group, dopaminergic (DA) neurons underwent extensive apoptotic cell death. The movement of Rab5a- or Rab7a-positive endosomes was slower, and the endosome fission and fusion frequencies were lower in the PD group than in the healthy control group. Interestingly, vesicles positive for cation-independent mannose 6-phosphate receptor transported by retromers were abnormally localized in glial cells derived from patient iPSCs. Furthermore, we found a-synuclein accumulation in TH positive DA neurons. Our results demonstrate the induction of cell death, endosomal dysfunction and a-synuclein accumulation in neural cells of the PD group. PARK17 patient-derived iPSCs provide an excellent experimental tool for understanding the pathophysiology underlying PD.

Endosomal recycling and dopamine neurotransmission: Exploring the links between the retromer and Parkinson's disease

“…Furthermore, several defects in endosomal function were observed, including impaired endosomal transport of both early and late endosomes, and impaired endosomal fission and fusion, although no differences in the association of retromer with endosomes were detected in neurons cultured from hIPSCs from patients versus controls. Intriguingly, an increase in intracellular α‐synuclein was also observed in the cytoplasm of differentiated DA hIPSC neurons, mirroring what is observed in some PD patient brains upon autopsy (Bono et al., 2020). In a more recent study from hIPSC neurons derived from fibroblasts of participants that carry the VPS35 D620N mutation, increased α‐synuclein accumulation was also observed in neurons compared with hIPSC neurons healthy controls (Hanss et al., 2021).…”

“…Owing to the difficulty of monitoring lysosomal and mitochondrial health in vivo, several groups have explored VPS35 D620N's effect on DA neuron vulnerability, organelle homeostasis, and PD, through the use of human‐induced pluripotent stem cells (hIPSCs). Indeed, in DA neurons generated from peripheral blood mononuclear cells of participants with PD that carry the VPS35 D620N mutation, increased apoptosis was observed compared with those cells from healthy controls (Bono et al., 2020). Furthermore, several defects in endosomal function were observed, including impaired endosomal transport of both early and late endosomes, and impaired endosomal fission and fusion, although no differences in the association of retromer with endosomes were detected in neurons cultured from hIPSCs from patients versus controls.…”

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

“…SAMM50 provides the required specificity to eliminate mtDNA while VPS35 supplies the selectivity. Interestingly, mutations in TWNK, ATAD3A, and VPS35 are linked to several severe mitochondrial diseases having in common mtDNA instability [72][73][74] , therefore representing a cluster of proteins involved in specific mtDNA turnover.…”