Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's disease

Paolo Calabresi, Alessandro Tozzi, Michela Tantucci, Saverio Marchi, Petra Mazzocchetti, Michele Morari, Paolo Pinton, Andrea Mancini

Risultato della ricerca: Contributo in rivistaArticolo in rivista

14 Citazioni (Scopus)

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor rotenone. This detrimental effect is reversed by the D2 DA receptor agonist quinpirole via the inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong rotenone-induced oxidative stress characterized by reduced Ca2+ buffering capability and ATP synthesis, production of reactive oxygen species, and increased mitochondrial fragmentation. Importantly, quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function, via the inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2 kinase domain and mitochondrial functionality.
Lingua originaleEnglish
pagine (da-a)1-13
Numero di pagine13
RivistaCELL DEATH & DISEASE
Volume9
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Animals
  • Corpus Striatum
  • Disease Models, Animal
  • Dopamine
  • Dopaminergic Neurons
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Male
  • Mesencephalon
  • Mice
  • Mice, Mutant Strains
  • Neuroprotection
  • Parkinson Disease
  • Receptors, Dopamine D2

Fingerprint

Entra nei temi di ricerca di 'Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson's disease'. Insieme formano una fingerprint unica.

Cita questo