Poul Henning Jensen

Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Michael Aagaard Andersen
  • ,
  • Kenneth Vielsted Christensen, Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.
  • ,
  • Lassina Badolo, Department of Discovery DMPK, H. Lundbeck A/S, Valby, Denmark.
  • ,
  • Garrick Paul Smith, Department of Discovery Chemistry 2, H. Lundbeck A/S, Valby, Denmark.
  • ,
  • Ross Jeggo, Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.
  • ,
  • Poul Henning Jensen
  • Kathrine Just Andersen, Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.
  • ,
  • Florence Sotty, Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.

Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.

Original languageEnglish
JournalNeurobiology of Disease
Volume116
Pages (from-to)13-27
Number of pages15
ISSN0969-9961
DOIs
Publication statusPublished - Aug 2018

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