Upregulation of Cathepsin D in the caudate nucleus of primates with experimental parkinsonism

Sowmya V Yelamanchili, Amrita Chaudhuri, Claudia T. Flynn, Howard S Fox

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease. Results: Using chronic 1-methyl-4phenyl-1,2,3, 6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis. Conclusions: Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.

Original languageEnglish (US)
Article number52
JournalMolecular neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - Jul 26 2011

Fingerprint

Cathepsin D
Caudate Nucleus
Parkinsonian Disorders
Primates
Up-Regulation
Substantia Nigra
Lysosomes
Parkinson Disease
Disease Progression
Dopaminergic Neurons
Brain
Caspases
Macaca mulatta
Neuroblastoma
Cognition
Haplorhini
Fluorescent Antibody Technique
Peptide Hydrolases
Apoptosis
Neurons

Keywords

  • MPTP
  • Parkinson's
  • apoptosis
  • cathepsin
  • caudate
  • neurodegeneration
  • nonhuman primate
  • striatum

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Upregulation of Cathepsin D in the caudate nucleus of primates with experimental parkinsonism. / Yelamanchili, Sowmya V; Chaudhuri, Amrita; Flynn, Claudia T.; Fox, Howard S.

In: Molecular neurodegeneration, Vol. 6, No. 1, 52, 26.07.2011.

Research output: Contribution to journalArticle

@article{c7ca8c73908b44a79ceb01053b4a883a,
title = "Upregulation of Cathepsin D in the caudate nucleus of primates with experimental parkinsonism",
abstract = "Background: In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease. Results: Using chronic 1-methyl-4phenyl-1,2,3, 6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis. Conclusions: Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.",
keywords = "MPTP, Parkinson's, apoptosis, cathepsin, caudate, neurodegeneration, nonhuman primate, striatum",
author = "Yelamanchili, {Sowmya V} and Amrita Chaudhuri and Flynn, {Claudia T.} and Fox, {Howard S}",
year = "2011",
month = "7",
day = "26",
doi = "10.1186/1750-1326-6-52",
language = "English (US)",
volume = "6",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Upregulation of Cathepsin D in the caudate nucleus of primates with experimental parkinsonism

AU - Yelamanchili, Sowmya V

AU - Chaudhuri, Amrita

AU - Flynn, Claudia T.

AU - Fox, Howard S

PY - 2011/7/26

Y1 - 2011/7/26

N2 - Background: In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease. Results: Using chronic 1-methyl-4phenyl-1,2,3, 6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis. Conclusions: Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.

AB - Background: In Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease. Results: Using chronic 1-methyl-4phenyl-1,2,3, 6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis. Conclusions: Following damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.

KW - MPTP

KW - Parkinson's

KW - apoptosis

KW - cathepsin

KW - caudate

KW - neurodegeneration

KW - nonhuman primate

KW - striatum

UR - http://www.scopus.com/inward/record.url?scp=79960566099&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960566099&partnerID=8YFLogxK

U2 - 10.1186/1750-1326-6-52

DO - 10.1186/1750-1326-6-52

M3 - Article

C2 - 21777416

AN - SCOPUS:79960566099

VL - 6

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 52

ER -