English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication.

Flierl, A., Oliveira, L. M. A., Falomir-Lockhart, L. J., Mak, S. K., Hesley, J., Soldner, F., et al. (2014). Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication. PLoS One, 9(11): e112413. doi:10.1371/journal.pone.0112413.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0024-3EF6-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CC74-2
Genre: Journal Article

Files

show Files
hide Files
:
2072786.pdf (Publisher version), 12MB
Name:
2072786.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Creators

show
hide
 Creators:
Flierl, A., Author
Oliveira, L. M. A.1, Author              
Falomir-Lockhart, L. J.1, Author              
Mak, S. K., Author
Hesley, J., Author
Soldner, F., Author
Arndt-Jovin, D. J.1, Author              
Jaenisch, R., Author
Langston, J. W., Author
Jovin, T. M.1, Author              
Schüle, B., Author
Affiliations:
1Emeritus Group Laboratory of Cellular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578628              

Content

show
hide
Free keywords: -
 Abstract: Parkinson disease (PD) is a multi-factorial neurodegenerative disorder with loss of dopaminergic neurons in the substantia nigra and characteristic intracellular inclusions, called Lewy bodies. Genetic predisposition, such as point mutations and copy number variants of the SNCA gene locus can cause very similar PD-like neurodegeneration. The impact of altered α-synuclein protein expression on integrity and developmental potential of neuronal stem cells is largely unexplored, but may have wide ranging implications for PD manifestation and disease progression. Here, we investigated if induced pluripotent stem cell-derived neuronal precursor cells (NPCs) from a patient with Parkinson's disease carrying a genomic triplication of the SNCA gene (SNCA-Tri). Our goal was to determine if these cells these neuronal precursor cells already display pathological changes and impaired cellular function that would likely predispose them when differentiated to neurodegeneration. To achieve this aim, we assessed viability and cellular physiology in human SNCA-Tri NPCs both under normal and environmentally stressed conditions to model in vitro gene-environment interactions which may play a role in the initiation and progression of PD. Human SNCA-Tri NPCs displayed overall normal cellular and mitochondrial morphology, but showed substantial changes in growth, viability, cellular energy metabolism and stress resistance especially when challenged by starvation or toxicant challenge. Knockdown of α-synuclein in the SNCA-Tri NPCs by stably expressed short hairpin RNA (shRNA) resulted in reversal of the observed phenotypic changes. These data show for the first time that genetic alterations such as the SNCA gene triplication set the stage for decreased developmental fitness, accelerated aging, and increased neuronal cell loss. The observation of this "stem cell pathology" could have a great impact on both quality and quantity of neuronal networks and could provide a powerful new tool for development of neuroprotective strategies for PD.

Details

show
hide
Language(s): eng - English
 Dates: 2014-11-12
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pone.0112413
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: PLoS One
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: 15 Volume / Issue: 9 (11) Sequence Number: e112413 Start / End Page: - Identifier: -