Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction

Chedid, Jessica ; Li, Yan ; Labrador-Garrido, Adahir ; Abu-Bonsrah, Dad ; Pavan, Chiara ; Fraser, Tyra ; Ovchinnikov, Dmitry ; Zhong, Melanie ; Davis, Ryan and Strbenac, Dario , et al. (2025) In npj Parkinson's Disease 11(1).
Abstract

Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those with SNCA mutations have increased alpha-synuclein deposition, while those with LRRK2 mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. To compare cellular dysfunctions associated with these different pathological phenotypes, an unbiased high-content imaging platform was developed to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition using induced pluripotent stem... (More)

Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those with SNCA mutations have increased alpha-synuclein deposition, while those with LRRK2 mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. To compare cellular dysfunctions associated with these different pathological phenotypes, an unbiased high-content imaging platform was developed to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition using induced pluripotent stem cell (iPSC) derived cortical and ventral midbrain neurons. Different PD mutations caused cell type specific dysfunctions, likely to impact on both selective neuronal vulnerability and the pathologies observed in PD. Comparison of dopamine neurons identified that both lysosomal and mitochondrial dysfunction were predominant with PRKN lof mutations, whereas SNCA A53T and LRRK2 R1441G mutations had increased tau deposition. In contrast, cortical neurons with SNCA and LRRK2 mutations both had mitochondrial and autophagy impairments without protein deposition, with LRRK2 cells additionally showing decreased glucocerebrosidase activity and increased alpha-synuclein phosphorylation.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
npj Parkinson's Disease
volume
11
issue
1
article number
177
publisher
Springer Nature
external identifiers
  • pmid:40541941
  • scopus:105008575909
ISSN
2373-8057
DOI
10.1038/s41531-025-01048-2
language
English
LU publication?
yes
id
ee997794-850d-46a9-bddb-b34c6faab67b
date added to LUP
2025-10-28 11:15:35
date last changed
2025-10-29 03:00:09
@article{ee997794-850d-46a9-bddb-b34c6faab67b,
  abstract     = {{<p>Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those with SNCA mutations have increased alpha-synuclein deposition, while those with LRRK2 mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. To compare cellular dysfunctions associated with these different pathological phenotypes, an unbiased high-content imaging platform was developed to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition using induced pluripotent stem cell (iPSC) derived cortical and ventral midbrain neurons. Different PD mutations caused cell type specific dysfunctions, likely to impact on both selective neuronal vulnerability and the pathologies observed in PD. Comparison of dopamine neurons identified that both lysosomal and mitochondrial dysfunction were predominant with PRKN lof mutations, whereas SNCA A53T and LRRK2 R1441G mutations had increased tau deposition. In contrast, cortical neurons with SNCA and LRRK2 mutations both had mitochondrial and autophagy impairments without protein deposition, with LRRK2 cells additionally showing decreased glucocerebrosidase activity and increased alpha-synuclein phosphorylation.</p>}},
  author       = {{Chedid, Jessica and Li, Yan and Labrador-Garrido, Adahir and Abu-Bonsrah, Dad and Pavan, Chiara and Fraser, Tyra and Ovchinnikov, Dmitry and Zhong, Melanie and Davis, Ryan and Strbenac, Dario and Johnston, Jennifer A. and Thompson, Lachlan H. and Kirik, Deniz and Parish, Clare L. and Halliday, Glenda M. and Sue, Carolyn M. and Wali, Gautam and Dzamko, Nicolas}},
  issn         = {{2373-8057}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer Nature}},
  series       = {{npj Parkinson's Disease}},
  title        = {{Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction}},
  url          = {{http://dx.doi.org/10.1038/s41531-025-01048-2}},
  doi          = {{10.1038/s41531-025-01048-2}},
  volume       = {{11}},
  year         = {{2025}},
}