Investigating the Molecular Pathogenic Mechanism Underlying Mutant VPS35-Induced Parkinson’s Disease

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Parkinson’s disease (PD) affects 〜1 % of the population above the age of 60 and is the most common neurodegenerative motor disease. The majority (〜90 %) of PD cases is sporadic, and hereditary forms of PD account for 〜10 % of PD patients. Patients with familial type 17 of Parkinson’s disease (PARK17) exhibit late-onset parkinsonism symptoms and autosomal dominant inheritance. Previous studies identified missense mutations of VPS35 (Vacuolar protein sorting 35) as the cause of PARK17. VPS35 mutations are the second most common genetic cause of late-onset familial PD after LRRK2 mutations. (D620N) mutation of VPS35 is a confirmed genetic cause of PARK17. Interestingly, (D620N) mutation of VPS35 was also observed in sporadic PD patients, suggesting that common molecular mechanisms are involved in the pathogenesis of PARK17 and sporadic PD. A better understanding of the molecular mechanism underlying mutant (D620N) VPS35-induced parkinsonism is expected to unravel the pathogenic mechanism of PARK17 and sporadic PD. Wnt/p-catenin signaling plays an essential role in the protection and survival of substantia nigra (SN) dopaminergic neurons. Multiple lines of evidence suggest that an impairment of neuroprotective Wnt/p-catenin signaling pathway increases the vulnerability of SN dopaminergic cells and causes the degeneration of SN dopaminergic neurons and resulting PD. Wnt signaling cascades are also believed to play an important role in regulating glutamatergic neurotransmission and GABAergic transmission in SN dopaminergic neurons. It is likely that impairment of Wnt signaling pathways causes the dysfunction of SN dopaminergic neurons by altering glutamatergic transmission and GABAergic neurotransmission, leading to an impaired motor function of nigrostriatal dopaminergic pathway and resulting parkinsonism. VPS35-containing retromer complex plays an essential role in the normal secretion of Wnt ligands by recycling Wntless, which is essential for Wnt secretion, from endosomes to the trans-Golgi network. Thus, the normal function of VPS35 is required for Wnt secretion and Wnt signaling activity. (D620N) VPS35 mutation disrupted the cargo sorting function of retromer and caused the trafficking defects. (D620N) mutation in VPS35 has also been shown to impair VPS35-mediated protection against MPP+ neurotoxicity. Therefore, (D620N) mutation induces the loss of VPS35-mediated physiological functions. It is reasonable to hypothesize that (D620N) VPS35 mutation causes an impaired activity of the retromer complex, the accumulation of Wntless in the endosomal system, the degradation of Wntless in the lysosomes and reduced secretion of Wnt, leading to an impaired Wnt signaling activity and resulting degeneration and synaptic dysfunction of SN dopaminergic neurons. In the present study, we will investigate the molecular pathogenic mechanism underlying mutant (D620N) VPS35-induced PD by performing the following experiments: (1) Mouse model of mutant (D620N) VPS35-induced PD is prepared by generating knockin mice expressing mutant (D620N) VPS35. Then, various methods are performed to confirm that VPS35D620N/+ knockin mice display the phenotypes of PD. (2) It is hypothesized that mutant (D620N) VPS35 causes an impairment of Wnt/p-catenin signaling cascade and resulting PD. To prove this hypothesis, in v^-vo experiments using VPS35D620N/+ mice or in vitro experiments using primary culture of SN are performed to provide the evidence that mutant (D620N) VPS35 impairs the activity of Wnt/p-catenin signaling pathway and induces the degeneration of SN dopaminergic neurons. (3) Wnt signaling pathways are likely to play an important role in regulating synaptic transmission in SN dopaminergic neurons. Therefore, mutant (D620N) VPS35-induced impairment of Wnt signaling could also cause an early-phase synaptic dysfunction of SN dopaminergic neurons and resulting parkinsonism. To test this hypothesis, we will investigate mutant (D620N) VPS35-induced alteration in glutamatergic transmission and GABAergic neurotransmission of SN dopaminergic neurons of VPS35 knockin mice.

Project IDs

Project ID:PC10501-1870
External Project ID:MOST104-2320-B182-014-MY3
StatusFinished
Effective start/end date01/08/1631/07/17

Keywords

  • Parkinson
  • s disease
  • Familial type 17 of Parkinson
  • s disease (PARK17)
  • Vacuolar

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