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 α-synuclein accumulation in TH positive DA neurons. Our results demonstrate the induction of cell death, endosomal dysfunction and α -synuclein accumulation in neural cells of the PD group. PARK17 patient-derived iPSCs provide an excellent experimental tool for understanding the pathophysiology underlying PD.
Highlights
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD), affects more than 2% of adults over 60 [1, 2]
We generated Induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of two PD patients carrying the D620N mutation in the Vacuolar protein sorting 35 (VPS35) gene (PD1 and PD2) and two healthy controls (Ctrl1 and Ctrl2)
In the current study, we show that the VPS35 mutation (D620N) decreased the velocity and deficits in fission and fusion in endosomes from iNeurons
Summary
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD), affects more than 2% of adults over 60 [1, 2]. PD is characterized by progressive motor symptoms such as bradykinesia, resting tremor, muscular rigidity, and postural instability (these four symptoms are called “parkinsonism”), as well as nonmotor symptoms such as olfactory dysfunction, autonomic dysfunction, and dementia [3]. PD is predominantly an idiopathic disease, with the largest risk factor being age; up to 10% of cases occur in a familial manner by both autosomal dominant and recessive transmission. Mutations in several pathogenic genes have been identified over the last two decades and found to be associated with both familial and sporadic PD. Mutations in α-synuclein ( called PARK1) and leucine-rich repeat kinase 2 (LRRK2 or PARK8) cause autosomal dominant PD, and mutations in parkin (PARK2), DJ-1 (PARK7), Pink (PARK6), and ATP13A2 (PARK9) have been linked to autosomal recessive PD [6,7,8].
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