Abstract
Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.
Original language | English (US) |
---|---|
Article number | 763777 |
Journal | Frontiers in Molecular Neuroscience |
Volume | 14 |
DOIs | |
State | Published - Nov 11 2021 |
Keywords
- Parkinson’s disease
- RNA sequencing
- cell death
- disease duration
- gene expression
- neurodegenerative disease
- neuroprotection
ASJC Scopus subject areas
- Molecular Biology
- Cellular and Molecular Neuroscience
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Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients. / Tiklová, Katarína; Gillberg, Linda; Volakakis, Nikolaos et al.
In: Frontiers in Molecular Neuroscience, Vol. 14, 763777, 11.11.2021.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients
AU - Tiklová, Katarína
AU - Gillberg, Linda
AU - Volakakis, Nikolaos
AU - Lundén-Miguel, Hilda
AU - Dahl, Lina
AU - Serrano, Geidy E.
AU - Adler, Charles H.
AU - Beach, Thomas G.
AU - Perlmann, Thomas
N1 - Funding Information: This work was supported by grants from Knut and Alice Wallenberg Foundation (TP; 2013.0075), from the Swedish Research Council (VR 2016-02506 and VR 2020-00884), from Torsten Söderbergs Stiftelse (TP; Akademiprofessur 2017), and from the Michael J. Fox Foundation for Parkinson’s Research (Grant ID 9032.01). KT was supported by a fellowship from the Swedish Society for Medical Research (SSMF). The Brain and Body donation program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026); National Brain and Tissue Resource for Parkinson’s Disease and Related Funding Information: This work was supported by grants from Knut and Alice Wallenberg Foundation (TP; 2013.0075), from the Swedish Research Council (VR 2016-02506 and VR 2020-00884), from Torsten S?derbergs Stiftelse (TP; Akademiprofessur 2017), and from the Michael J. Fox Foundation for Parkinson?s Research (Grant ID 9032.01). KT was supported by a fellowship from the Swedish Society for Medical Research (SSMF). The Brain and Body donation program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026); National Brain and Tissue Resource for Parkinson?s Disease and Related Disorders; National Institute on Aging (P30 AG19610); Arizona Alzheimer?s Disease Core Center; Arizona Department of Health Services, Arizona Alzheimer?s Consortium; Arizona Biomedical Research Commission, Arizona Parkinson?s Disease Consortium; and Michael J. Fox Foundation for Parkinson?s Research. Funding Information: Gibb, W. R., and Lees, A. J. (1988). The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 51:745. doi: 10.1136/jnnp.51.6.745 Gibb, W. R., and Lees, A. J. (1991). Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J. Neurol. Neurosurg. 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Neuroprotective role of the basic Leucine Zipper transcription factor NFIL3 in models of amyotrophic lateral sclerosis∗∗ this work was supported in part by grants-in-aid from the ministry of education, culture, sports, science, and technology of Japan (to N. K., Y. F., and K. S.) and by an operating grant from the Canadian institutes of health research (to M. D. N). J. Biol. Chem. 289, 1629–1638. doi: 10.1074/jbc.m113.524389 Tansey, M. G., and Goldberg, M. S. (2010). Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37, 510–518. doi: 10.1016/j.nbd.2009.11.004 Wang, D., Zhai, J.-X., Zhang, L.-M., and Liu, D.-W. (2014). Null genotype of GSTT1 contributes to increased Parkinson’s disease risk in Caucasians: evidence from a meta-analysis. Mol. Biol. Rep. 41, 7423–7430. doi: 10.1007/s11033-014-3631-6 Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., et al. (2010). PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci. Transl. Med. 2:52ra73. doi: 10.1126/scitranslmed. 3001059 Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher Copyright: Copyright © 2021 Tiklová, Gillberg, Volakakis, Lundén-Miguel, Dahl, Serrano, Adler, Beach and Perlmann.
PY - 2021/11/11
Y1 - 2021/11/11
N2 - Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.
AB - Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.
KW - Parkinson’s disease
KW - RNA sequencing
KW - cell death
KW - disease duration
KW - gene expression
KW - neurodegenerative disease
KW - neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=85120402282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120402282&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2021.763777
DO - 10.3389/fnmol.2021.763777
M3 - Article
AN - SCOPUS:85120402282
VL - 14
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
SN - 1662-5099
M1 - 763777
ER -