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Related Concept Videos

Parkinson Disease ll: Pathophysiology01:24

Parkinson Disease ll: Pathophysiology

Parkinson disease (PD) is a progressive neurodegenerative disorder primarily affecting movement, with additional non-motor features. Its pathophysiology involves complex interactions among genetic susceptibility, environmental exposures, and cellular dysfunction, including dopaminergic neuron loss, protein aggregation, and mitochondrial impairment.Selective NeurodegenerationA key feature is the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced...

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Related Experiment Video

Updated: Jun 25, 2026

Recombinant α- β- and γ-Synucleins Stimulate Protein Phosphatase 2A Catalytic Subunit Activity in Cell Free Assays
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Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo.

Valerie Cullen1, Maria Lindfors, Juliana Ng

  • 1Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. valerie_cullen@hotmail.com

Molecular Brain
|February 11, 2009
PubMed
Summary

Cathepsin D (CathD) degrades alpha-synuclein (aSyn) in cells. Mutations in the CTSD gene cause a lysosomal disorder, leading to aSyn misprocessing and increased toxicity, highlighting CathD

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Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains
09:27

Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains

Published on: January 5, 2016

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Elevated alpha-synuclein (aSyn) is linked to Parkinson disease (PD).
  • Limited understanding of enzymes involved in aSyn degradation.
  • Focus on Cathepsin D (CathD) encoded by the CTSD gene for aSyn processing.

Purpose of the Study:

  • Investigate the role of Cathepsin D (CathD) in alpha-synuclein (aSyn) processing.
  • Determine the impact of CTSD gene expression on aSyn levels and toxicity.
  • Explore CathD's potential as a therapeutic target for Parkinson disease.

Main Methods:

  • Over-expression of human CTSD cDNA in dopaminergic cell cultures.
  • Analysis of aSyn levels in ctsd knock-out mice using Western blotting and ELISA.
  • Immunohistochemical studies of ctsd-mutant brains (mice, sheep, humans).
  • Assessment of retinal toxicity in a ctsd-null Drosophila model.

Main Results:

  • CTSD over-expression led to dose-dependent proteolysis of aSyn.
  • CTSD deficiency resulted in reduced soluble aSyn but increased insoluble, oligomeric aSyn.
  • CTSD mutations caused synucleinopathy-like changes and enhanced retinal toxicity in Drosophila.
  • Ubiquitin-positive inclusions were observed in ctsd-mutant brains.

Conclusions:

  • CathD effectively degrades excess aSyn in dopaminergic cells.
  • CTSD mutations lead to a lysosomal storage disorder with aSyn misprocessing.
  • CathD deficiency exacerbates aSyn toxicity, suggesting CathD acts as a 'synucleinase'.