Vacuolar protein sorting 35 (Vps35) rescues locomotor deficits and shortened lifespan in Drosophila expressing a Parkinson’s disease mutant of Leucine-rich repeat kinase 2 (LRRK2)

Abstract

BackgroundParkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2).FindingsWe employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment.ConclusionsFrom these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Second, in all cases, the disease is caused by a loss rather than a gain of retromer function. This agrees with observations in yeast, neuronal culture, and animal models that have shown that, whereas a slight loss of retromer function has dramatic pathological consequences, increasing retromer levels seems to be either beneficial or innocuous [40]. This speaks to the concern that increasing retromer levels in many cells, be it genetically or pharmacologically, might have negative side effects.…”

Cellular processes associated with LRRK2 function and dysfunction

“…The pathogenic mutations, G2019S , R1441C and Y1699C enhanced Golgi clearance, but the hypothesis‐testing mutations that decrease GTP binding, the T1348N, or the kinase‐inactive K1906M, did not sustain Golgi clearance, suggesting that both kinase and GTPase activities are required for maintaining this cellular process 118. Overexpression of VPS35 exhibited protective effects in mutant LRRK2 Drosophila 132; it is of interest to note that mutations in the VPS35 encoding gene have been identified in PD families 133, 134, further implicating the disruption of retromer mediated protein sorting as potentially leading to PD.…”

VPS35-Linked Parkinson’s Disease Resembles the Idiopathic Disease: A Review of Clinical Trials

“…While within the last half decade we considerably learned about the genetics of VPS35 patients, we have nothing at hand to offer our clinical VPS35 patients. More human case reports including neuropathology would be needed to find a specific clinical marker of VPS35 patients to allow a targeted referral to genetic testing [22][23][24][25][26].…”