Emergent glutamate & dopamine dysfunction in VPS35(D620N) knock-in mice and rapid reversal by LRRK2 inhibition

A Kamesh; C A Kadgien; N Kuhlmann; S Coady; A Pietrantonio; Y Cousineau; A Khayachi; A Jurado Santos; E P Hurley; J C Barron; M P Parsons; A J Milnerwood

doi:10.1038/s41531-025-00948-7

Emergent glutamate & dopamine dysfunction in VPS35_(D620N) knock-in mice and rapid reversal by LRRK2 inhibition

NPJ Parkinsons Dis. 2025 May 3;11(1):106. doi: 10.1038/s41531-025-00948-7.

Authors

A Kamesh¹, C A Kadgien^{2

3}, N Kuhlmann^{2

3}, S Coady², A Pietrantonio², Y Cousineau², A Khayachi², A Jurado Santos⁴, E P Hurley⁵, J C Barron⁵, M P Parsons⁵, A J Milnerwood^{6

7}

Affiliations

¹ The Neuro, McGill University, Montreal, QC, Canada. anusha.kamesh@mail.mcgill.ca.
² The Neuro, McGill University, Montreal, QC, Canada.
³ Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.
⁴ Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
⁵ Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NF, Canada.
⁶ The Neuro, McGill University, Montreal, QC, Canada. austen.milnerwood@mcgill.ca.
⁷ Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada. austen.milnerwood@mcgill.ca.

Abstract

The D620N variant in Vacuolar Protein Sorting 35 (VPS35) causes autosomal-dominant, late-onset Parkinson's disease. VPS35 is a core subunit of the retromer complex that canonically recycles transmembrane cargo from sorting endosomes. Although retromer cargoes include many synaptic proteins, VPS35's neuronal functions are poorly understood. To investigate the consequences of the Parkinson's mutation, striatal neurotransmission was assessed in 1- to 6-month-old VPS35 D620N knock-in (VKI) mice. Spontaneous and optogenetically-evoked corticostriatal glutamate transmission was increased in VKI spiny projection neurons by 6 months and was unaffected by acute leucine-rich repeat kinase 2 (LRRK2) inhibition. Total striatal glutamate release by iGluSnFR imaging was similar to wild-type. dLight imaging revealed robust increases in VKI striatal dopamine release by 6 months, which were reversed with acute LRRK2 kinase inhibition. We conclude that increased striatal neurotransmission in VKI mice progressively emerges in young-adulthood, and that dopamine dysfunction is likely the result of sustained, rapidly-reversible, LRRK2 hyperactivity.