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Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease

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Listed:
  • Qingde Zhou

    (Boston University School of Medicine)

  • Allen Yen

    (Boston University School of Medicine)

  • Grzegorz Rymarczyk

    (Boston University School of Medicine)

  • Hirohide Asai

    (Boston University School of Medicine)

  • Chelsea Trengrove

    (Boston University School of Medicine)

  • Nadine Aziz

    (Boston University School of Medicine)

  • Michael T. Kirber

    (Boston University School of Medicine)

  • Gustavo Mostoslavsky

    (Center for Regenerative Medicine, Boston University School of Medicine)

  • Tsuneya Ikezu

    (Boston University School of Medicine)

  • Benjamin Wolozin

    (Boston University School of Medicine)

  • Victoria M. Bolotina

    (Boston University School of Medicine)

Abstract

The etiology of idiopathic Parkinson’s disease (idPD) remains enigmatic despite recent successes in identification of genes (PARKs) that underlie familial PD. To find new keys to this incurable neurodegenerative disorder we focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and the store-operated Ca2+ signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca2+ signalling, which we can mimic in a novel B6.Cg-Pla2g6ΔEx2-VB (PLA2g6 ex2KO) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6-dependent Ca2+ signalling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction. Discovery of this previously unknown sequence of pathological events, its association with idPD and our ability to mimic this pathology in a novel genetic mouse model opens new opportunities for finding a cure for this devastating neurodegenerative disease.

Suggested Citation

  • Qingde Zhou & Allen Yen & Grzegorz Rymarczyk & Hirohide Asai & Chelsea Trengrove & Nadine Aziz & Michael T. Kirber & Gustavo Mostoslavsky & Tsuneya Ikezu & Benjamin Wolozin & Victoria M. Bolotina, 2016. "Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10332
    DOI: 10.1038/ncomms10332
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