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PMID:26392287

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Citation

Rocha, EM, Smith, GA, Park, E, Cao, H, Brown, E, Hayes, MA, Beagan, J, McLean, JR, Izen, SC, Perez-Torres, E, Hallett, PJ and Isacson, O (2015) Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons. Neurobiol. Dis. 82:495-503

Abstract

Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including α-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related α-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of α-synuclein and protect midbrain dopamine neurons from α-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype α-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant α-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of α-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T α-synuclein into the substantia nigra prevented α-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of α-synuclein.

Links

PubMed Online version:10.1016/j.nbd.2015.09.009

Keywords

Animals; Dependovirus/genetics; Disease Models, Animal; Dopamine/metabolism; Dopaminergic Neurons/enzymology; Dopaminergic Neurons/pathology; Female; Genetic Therapy/methods; Genetic Vectors; Glucosylceramidase/genetics; Glucosylceramidase/metabolism; Humans; Male; Mesencephalon/enzymology; Mesencephalon/pathology; Mice, Transgenic; Neurodegenerative Diseases/enzymology; Neurodegenerative Diseases/pathology; Neurodegenerative Diseases/therapy; Rats, Sprague-Dawley; alpha-Synuclein/genetics; alpha-Synuclein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GLCM

involved_in

GO:0031333: negative regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002038)|has_input(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:0051247: positive regulation of protein metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P37840

P

  • has_input:(UniProtKB:Q13501)
  • regulates_o_occurs_in:(UBERON:0002038)
  • part_of:(GO:0035967)|has_input(UniProtKB:Q13501)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:0043243: positive regulation of protein-containing complex disassembly

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002038)|has_input(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:1903061: positive regulation of protein lipidation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P37840

P

  • has_input:(UniProtKB:Q9H492)
  • regulates_o_occurs_in:(UBERON:0002038)
  • part_of:(GO:0035967)|has_input(UniProtKB:Q9H492)
  • regulates_o_occurs_in:(UBERON:0002435)
  • part_of:(GO:0035967)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:0051247: positive regulation of protein metabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P37840

P

  • has_regulation_target:(UniProtKB:Q13501)
  • regulates_o_occurs_in:(UBERON:0002038)
  • part_of:(GO:0035967)|has_regulation_target(UniProtKB:Q13501)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:1903061: positive regulation of protein lipidation

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P37840

P

  • has_regulation_target:(UniProtKB:Q9H492)
  • regulates_o_occurs_in:(UBERON:0002038)
  • part_of:(GO:0035967)|has_regulation_target(UniProtKB:Q9H492)
  • regulates_o_occurs_in:(UBERON:0002435)
  • part_of:(GO:0035967)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:0043243: positive regulation of protein complex disassembly

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002038)|has_regulation_target(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:1901215: negative regulation of neuron death

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P37840

P

  • regulates_o_occurs_in:(CL:0002614)
  • part_of:(GO:0035967)

Seeded From UniProt

complete

HUMAN:GLCM

involved_in

GO:0032463: negative regulation of protein homooligomerization

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002038)|has_regulation_target(UniProtKB:P37840)
  • regulates_o_occurs_in:(UBERON:0002435)

Seeded From UniProt

complete

Notes

See also

References

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