LINE-1 activation in the cerebellum drives ataxia.
Neuron
; 110(20): 3278-3287.e8, 2022 10 19.
Article
in En
| MEDLINE
| ID: mdl-36070749
ABSTRACT
Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Transposable Elements
/
Reverse Transcriptase Inhibitors
Limits:
Animals
/
Humans
Language:
En
Journal:
Neuron
Journal subject:
NEUROLOGIA
Year:
2022
Document type:
Article
Affiliation country: