α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies

Hum Mol Genet. 2024 Jul 22;33(15):1328-1338. doi: 10.1093/hmg/ddae073.

Abstract

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.

Keywords: Drosophila melanogaster; Rop; STXBP1; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Diseases / genetics
  • Brain Diseases / metabolism
  • Brain Diseases / pathology
  • Disease Models, Animal*
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster* / genetics
  • Haploinsufficiency* / genetics
  • Humans
  • Munc18 Proteins* / genetics
  • Munc18 Proteins* / metabolism
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Synucleinopathies / genetics
  • Synucleinopathies / metabolism
  • Synucleinopathies / pathology
  • Trehalose / metabolism
  • alpha-Synuclein* / genetics
  • alpha-Synuclein* / metabolism

Substances

  • alpha-Synuclein
  • Munc18 Proteins
  • Drosophila Proteins
  • STXBP1 protein, human
  • Trehalose