Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons Article Swipe
Doron D. Sommer
,
Sandeep Rajkumar
,
Mira Seidel
,
Amr Aly
,
Albert C. Ludolph
,
Ritchie Ho
,
Tobias M. Boeckers
,
Alberto Catanese
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.3389/fnmol.2022.894230
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.3389/fnmol.2022.894230
Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by dysfunction and loss of upper and lower motor neurons (MN). Despite several studies identifying drastic alterations affecting synaptic composition and functionality in different experimental models, the specific contribution of impaired activity to the neurodegenerative processes observed in ALS-related MN remains controversial. In particular, contrasting lines of evidence have shown both hyper- as well as hypoexcitability as driving pathomechanisms characterizing this specific neuronal population. In this study, we combined high definition multielectrode array (HD-MEA) techniques with transcriptomic analysis to longitudinally monitor and untangle the activity-dependent alterations arising in human C9orf72-mutant MN. We found a time-dependent reduction of neuronal activity in ALS C9orf72 cultures occurring as synaptic contacts undergo maturation and matched by a significant loss of mutant MN upon aging. Notably, ALS-related neurons displayed reduced network synchronicity most pronounced at later stages of culture, suggesting synaptic imbalance. In concordance with the HD-MEA data, transcriptomic analysis revealed an early up-regulation of synaptic terms in ALS C9orf72 MN, whose expression was decreased in aged cultures. In addition, treatment of older mutant cells with Apamin, a K + channel blocker previously shown to be neuroprotective in ALS, rescued the time-dependent loss of firing properties observed in ALS C9orf72 MN as well as the expression of maturity-related synaptic genes. All in all, this study broadens the understanding of how impaired synaptic activity contributes to MN degeneration in ALS by correlating electrophysiological alterations to aging-dependent transcriptional programs.
Related Topics
Concepts
C9orf72
Amyotrophic lateral sclerosis
Neuroscience
Biology
Neuroprotection
Transcriptome
Synapse
Neurotransmission
Population
Gene expression
Genetics
Gene
Medicine
Disease
Trinucleotide repeat expansion
Internal medicine
Receptor
Allele
Environmental health
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3389/fnmol.2022.894230
- OA Status
- gold
- Cited By
- 22
- References
- 58
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4282940692
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4282940692Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.3389/fnmol.2022.894230Digital Object Identifier
- Title
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Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor NeuronsWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2022Year of publication
- Publication date
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2022-06-14Full publication date if available
- Authors
-
Doron D. Sommer, Sandeep Rajkumar, Mira Seidel, Amr Aly, Albert C. Ludolph, Ritchie Ho, Tobias M. Boeckers, Alberto CataneseList of authors in order
- Landing page
-
https://doi.org/10.3389/fnmol.2022.894230Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://doi.org/10.3389/fnmol.2022.894230Direct OA link when available
- Concepts
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C9orf72, Amyotrophic lateral sclerosis, Neuroscience, Biology, Neuroprotection, Transcriptome, Synapse, Neurotransmission, Population, Gene expression, Genetics, Gene, Medicine, Disease, Trinucleotide repeat expansion, Internal medicine, Receptor, Allele, Environmental healthTop concepts (fields/topics) attached by OpenAlex
- Cited by
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22Total citation count in OpenAlex
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2025: 6, 2024: 10, 2023: 5, 2022: 1Per-year citation counts (last 5 years)
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58Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.transcriptional | 240 |
| abstract_inverted_index.hypoexcitability | 65 |
| abstract_inverted_index.maturity-related | 212 |
| abstract_inverted_index.neurodegenerative | 7, 44 |
| abstract_inverted_index.activity-dependent | 94 |
| abstract_inverted_index.electrophysiological | 236 |
| cited_by_percentile_year.max | 99 |
| cited_by_percentile_year.min | 89 |
| corresponding_author_ids | https://openalex.org/A5016988307 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 8 |
| corresponding_institution_ids | https://openalex.org/I196349391, https://openalex.org/I2801533059 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.6499999761581421 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.92193492 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |