Table 2.

Summary of pathological features of animal models of VPS35-linked PD

Model	Construct	Motor phenotype	Neuropathology	Cellular pathology	Reference
mouse KO (germline)	VPS35+/–	↓ performance in open field test (12 and 18 months)	∼20% DA neuron loss by12 months	↓ LAMP2a resulting in ↑ α-syn in DA neurons	[60]
			↑ α-syn levels in VM
mouse cKO	VPS35–/–/DAT-Cre	↓ performance in open field test	↓ DA neurons by 2–3 months	↓ levels of MFN2 resulting in impaired mitochondrial fusion	[56]
		Weak/unsteady gait	↑ α-syn levels in VM
		↓ hindlimb stepping
mouse KI (D620N)	VPS35D620N/D620N	None (∼5 months)	None (∼5 months)	↓ evoked striatal dopamine release	[62]
mouse viral-mediated gene transfer	Lentiviral vector expressing human VPS35D620N	Unknown	↓ in DA neurons compared to contralateral side	↑ mitochondrial fragmentation	[57]
rat viral-mediated gene transfer	AAV2/6-VPS35D620N (human)	None	∼30% DA neuron loss (12 weeks post-injection)	Neurite degeneration (Gallyas silver)	[54]
C. elegans deletion mutant	KN555 vps-35 (hu68) II	Unknown	impaired DA9 formation in the presence of A53T α-syn expression	genetic interaction of VPS35 and α-syn	[80]
Drosophila transgenic	ddc-Gal4 or GMR-Gal4/UAS-VPS35	Unknown	Unknown	Rescues mutant LRRK2 eye and locomotor phenotypes, protects against rotenone toxicity	[76]
Drosophila transgenic	ddc-Gal4/UAS-huVPS35D620N	↓ climbing ability	↓ in DA neurons at 60 days in PPL cluster	↑ sensitivity to rotenone toxicity	[58]
	da-Gal4 or hedgehog-Gal4/UAS- huVPS35D620N		Slight ↓ in lifespan	Rescues parkin KO phenotypes	[83]
Drosophila KO	vps35MH20/vps35E42	Larval locomotion defects	Defects in NMJ development	Mild eye disorganization in α-syn transgenic flies	[49, 83]
	RNAi-mediated VPS35 silencing		larval stage lethality	Exacerbates α-syn transgenic fly locomotor impairment
			melanotic masses

Abbreviations: KO, knockout; cKO, conditional knockout; KI, knockin; DA, dopaminergic; TH, tyrosine hydroxylase; VM, ventral midbrain; NMJ, neuromuscular junction; α-syn, α-synuclein