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DNA DAMAGE REPAIR DEFECTS IN AMYOTROPHIC LATERAL SCLEROSIS MOTOR NEURONS
Joris Van Lindtand 1 co-author
VIB-KU Leuven Center for Neuroscience
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-245
Presentation
Date TBA
Board: PS05-09AM-245
Event Information
Poster Board
PS05-09AM-245
Poster
View posterAbstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by the progressive loss of motor neurons, ultimately leading to paralysis and death. Emerging evidence suggests that accumulated defects in DNA damage repair contribute to motor neuron degeneration. However, the mechanisms linking dysregulated DNA repair to neurodegeneration—and whether these defects are a cause or consequence of disease—remain unclear.
To investigate DNA damage repair deficits, we employed iPSC-derived motor neurons from patients harboring C9ORF72 repeat expansions, the most common genetic cause of ALS, alongside their isogenic controls. DNA damage response was assessed using γ-H2AX, a well-known DNA damage response marker. Under basal conditions, ALS motor neurons displayed no difference in DNA damage response activation compared to controls. Remarkably, following DNA damage induced by inhibition of DNA topoisomerase I, ALS motor neurons exhibited impaired activation of the DNA damage response pathway. Furthermore, topoisomerase I inhibition disrupted additional neuronal phenotypes, including axonal transport and neurite outgrowth, underscoring the link between active DNA repair and motor neuron health.
In summary, our findings reveal a dysregulated DNA damage response in C9ORF72 ALS motor neurons and highlight its broader impact on neuronal function, offering new insights into mechanisms driving motor neuron vulnerability in ALS.
To investigate DNA damage repair deficits, we employed iPSC-derived motor neurons from patients harboring C9ORF72 repeat expansions, the most common genetic cause of ALS, alongside their isogenic controls. DNA damage response was assessed using γ-H2AX, a well-known DNA damage response marker. Under basal conditions, ALS motor neurons displayed no difference in DNA damage response activation compared to controls. Remarkably, following DNA damage induced by inhibition of DNA topoisomerase I, ALS motor neurons exhibited impaired activation of the DNA damage response pathway. Furthermore, topoisomerase I inhibition disrupted additional neuronal phenotypes, including axonal transport and neurite outgrowth, underscoring the link between active DNA repair and motor neuron health.
In summary, our findings reveal a dysregulated DNA damage response in C9ORF72 ALS motor neurons and highlight its broader impact on neuronal function, offering new insights into mechanisms driving motor neuron vulnerability in ALS.
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