Abstract
The mechanisms whereby mutant gene expression triggers neurodegeneration are poorly understood but have generally been attributed to translated gene products. We now demonstrate direct neuropathic effects of untranslated RNA on cultured motor neurons. We show that expression of untranslated light neurofilament (NF-L) RNA sequence in the 3′UTR of an EGFP transgene (pEGFP/NF-L RNA) or in a separate expression vector (pRc/NF-L RNA) causes dose-dependent, neuron-specific motor neuron degeneration. Neither unfused EGFP protein (pEGFP/wt) nor EGFP-tagged NF-L protein (pEGFP/NF-L protein) has similar neuropathic effects. The findings are the first demonstration of a direct RNA-mediated neurotoxic effect. Moreover, the resulting neuropathological changes show that untranslated RNA can lead to early degeneration of neuritic processes and accumulations of ubiquitinated aggregates in the perikarya and nuclei of degenerating motor neurons. The latter findings are hallmark neuropathological features of neurodegenerative diseases and their occurrence as a result of altered RNA expression raises the prospects of an RNA-mediated component in the pathogenesis of neurodegenerative states.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 936-950 |
| Number of pages | 15 |
| Journal | Journal of Neuropathology and Experimental Neurology |
| Volume | 62 |
| Issue number | 9 |
| State | Published - Sep 1 2003 |
| Externally published | Yes |
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Keywords
- Motor neuron degeneration
- Neurofilament RNA
- Neuropathological changes
- Primary motor neuron cultures
- RNA-mediated neurotoxicity
- Ubiquitinated neuronal inclusions
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Neuroscience(all)
Cite this
Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons. / Lin, Hong; Zhai, Jinbin; Nie, Zhenying (Jane); Wu, Junhua; Meinkoth, Judy L.; Schlaepfer, William W.; Cañete-Soler, Rafaela.
In: Journal of Neuropathology and Experimental Neurology, Vol. 62, No. 9, 01.09.2003, p. 936-950.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neurofilament RNA causes neurodegeneration with accumulation of ubiquitinated aggregates in cultured motor neurons
AU - Lin, Hong
AU - Zhai, Jinbin
AU - Nie, Zhenying (Jane)
AU - Wu, Junhua
AU - Meinkoth, Judy L.
AU - Schlaepfer, William W.
AU - Cañete-Soler, Rafaela
PY - 2003/9/1
Y1 - 2003/9/1
N2 - The mechanisms whereby mutant gene expression triggers neurodegeneration are poorly understood but have generally been attributed to translated gene products. We now demonstrate direct neuropathic effects of untranslated RNA on cultured motor neurons. We show that expression of untranslated light neurofilament (NF-L) RNA sequence in the 3′UTR of an EGFP transgene (pEGFP/NF-L RNA) or in a separate expression vector (pRc/NF-L RNA) causes dose-dependent, neuron-specific motor neuron degeneration. Neither unfused EGFP protein (pEGFP/wt) nor EGFP-tagged NF-L protein (pEGFP/NF-L protein) has similar neuropathic effects. The findings are the first demonstration of a direct RNA-mediated neurotoxic effect. Moreover, the resulting neuropathological changes show that untranslated RNA can lead to early degeneration of neuritic processes and accumulations of ubiquitinated aggregates in the perikarya and nuclei of degenerating motor neurons. The latter findings are hallmark neuropathological features of neurodegenerative diseases and their occurrence as a result of altered RNA expression raises the prospects of an RNA-mediated component in the pathogenesis of neurodegenerative states.
AB - The mechanisms whereby mutant gene expression triggers neurodegeneration are poorly understood but have generally been attributed to translated gene products. We now demonstrate direct neuropathic effects of untranslated RNA on cultured motor neurons. We show that expression of untranslated light neurofilament (NF-L) RNA sequence in the 3′UTR of an EGFP transgene (pEGFP/NF-L RNA) or in a separate expression vector (pRc/NF-L RNA) causes dose-dependent, neuron-specific motor neuron degeneration. Neither unfused EGFP protein (pEGFP/wt) nor EGFP-tagged NF-L protein (pEGFP/NF-L protein) has similar neuropathic effects. The findings are the first demonstration of a direct RNA-mediated neurotoxic effect. Moreover, the resulting neuropathological changes show that untranslated RNA can lead to early degeneration of neuritic processes and accumulations of ubiquitinated aggregates in the perikarya and nuclei of degenerating motor neurons. The latter findings are hallmark neuropathological features of neurodegenerative diseases and their occurrence as a result of altered RNA expression raises the prospects of an RNA-mediated component in the pathogenesis of neurodegenerative states.
KW - Motor neuron degeneration
KW - Neurofilament RNA
KW - Neuropathological changes
KW - Primary motor neuron cultures
KW - RNA-mediated neurotoxicity
KW - Ubiquitinated neuronal inclusions
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UR - http://www.scopus.com/inward/citedby.url?scp=0141455216&partnerID=8YFLogxK
M3 - Article
VL - 62
SP - 936
EP - 950
JO - American Journal of Psychotherapy
JF - American Journal of Psychotherapy
SN - 0002-9564
IS - 9
ER -