Vacuolar protein sorting-35 (VPS35) is a retromer component for endosomal trafficking. Mutations of VPS35 have been linked to familial Parkinson’s disease (PD). Here we showed that specific deletion of the VPS35 gene in DA neurons resulted in PD-like deficits including loss of DA neurons and accumulation of α-synuclein. Intriguingly, mitochondria became fragmented and mal-functional in VPS35-deficient DA neurons, phenotypes that could be restored by expressing VPS35 wild type, but not PD-linked mutant. Concomitantly, VPS35 deficiency or mutation increased mitochondrial E3 ubiquitin ligase-1 (MUL1) and thus led to mitofusin-2 (MFN2) degradation and mitochondrial fragmentation. Suppression of MUL1 expression ameliorated MFN2-reduction and DA neuron-loss, but not α-synuclein-accumulation. These results provide a cellular mechanism for VPS35-dysfunction in mitochondrial impairment and PD pathogenesis.
Vacuolar protein sorting-35 (VPS35) is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with autosomal dominant PD. However, it remains poorly understood if and how VPS35 deficiency or mutation contributes to PD pathogenesis. Here we provide evidence that links VPS35 deficiency to PD-like neuropathology. VPS35 was expressed in mouse dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and STR (striatum)-regions that are PD vulnerable. VPS35-deficient mice exhibited PD-relevant deficits including accumulation of ␣-synuclein in SNpc-DA neurons, loss of DA transmitter and DA neurons in SNpc and STR, and impairment of locomotor behavior. Further mechanical studies showed that VPS35-deficient DA neurons or DA neurons expressing PD-linked VPS35 mutant (D620N) had impaired endosome-to-Golgi retrieval of lysosome-associated membrane glycoprotein 2a (Lamp2a) and accelerated Lamp2a degradation. Expression of Lamp2a in VPS35-deficient DA neurons reduced ␣-synuclein, supporting the view for Lamp2a as a receptor of chaperone-mediated autophagy to be critical for ␣-synuclein degradation. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis and reveals a crucial pathway, VPS35-Lamp2a-␣-synuclein, to prevent PD pathogenesis.
The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.
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