Amyotrophic lateral sclerosis (ALS) is a devastating
neurodegenerative disease caused by the loss of motor neurons. The degenerating motor neurons of ALS patients are characterized by the accumulation of cytoplasmic inclusions containing phosphorylated and truncated forms of the
RNA-binding protein TDP-43.
Ataxin 2 intermediate-length
polyglutamine (
polyQ) expansions were recently identified as a risk factor for ALS; however, the mechanism by which they contribute to disease is unknown. Here, we show that intermediate-length
ataxin 2 polyQ expansions enhance stress-induced TDP-43 C-terminal cleavage and phosphorylation in human cells. We also connect intermediate-length
ataxin 2 polyQ expansions to the stress-dependent activation of multiple
caspases, including
caspase 3.
Caspase activation is upstream of TDP-43 cleavage and phosphorylation since
caspase inhibitors block these pathological modifications. Analysis of the accumulation of activated
caspase 3 in motor neurons revealed a striking association with ALS cases harboring
ataxin 2 polyQ expansions. These findings indicate that activated
caspase 3 defines a new pathological feature of ALS with intermediate-length
ataxin 2 polyQ expansions. These results provide mechanistic insight into how
ataxin 2 intermediate-length
polyQ expansions could contribute to ALS--by enhancing stress-induced TDP-43 pathological modifications via
caspase activation. Because longer
ataxin 2 polyQ expansions are associated with a different disease,
spinocerebellar ataxia 2, these findings help explain how different
polyQ expansions in the same
protein can have distinct cellular consequences, ultimately resulting in different clinical features. Finally, since
caspase inhibitors are effective at reducing TDP-43 pathological modifications, this pathway could be pursued as a therapeutic target in ALS.