19 September 2013. The amyotrophic lateral sclerosis gene FUS mends broken DNA strands, according to a paper in the September 15 Nature Neuroscience online. FUS has also been linked to frontotemporal dementia. As originally reported by Alzforum at a Keystone Symposium in February, Li-Huei Tsai and colleagues at MIT found that the protein FUS partners with histone deacetylase 1 (HDAC1) to patch up double-stranded DNA breaks. The finding fits with other lines of evidence pointing to genome fragmentation as a factor in several kinds of neurodegenerative disease (see Alzforum News story).
Having proposed a role for HDAC1 in DNA repair (see Alzforum News story on Kim et al., 2008), the Tsai lab next sought HDAC1 binding partners. The scientists identified FUS, a nucleic acid-binding protein mutated in some cases of ALS and FTD. HDAC1 and FUS bound more strongly in the presence of DNA damage in cultured primary mouse neurons.
In a human osteosarcoma cell line, FUS appeared on the scene of DNA damage inflicted with a laser within one minute of the break, and it then recruited HDAC1. Furthermore, knockdown of FUS both in the osteosarcoma line and in cultured mouse primary cortical neurons resulted in faulty DNA repair.
Autopsy brain tissue from two people who had had ALS due to FUS mutations showed excess DNA damage. The damage was most prominent in motor neurons in the spinal cord and pyramidal neurons in the motor cortex, less so in interneurons and glia, Tsai wrote in an email to Alzforum. “Motor neurons might be more sensitive because they are among the most active cells in the body,” she suggested.
Studies of cultured osteosarcoma cells expressing mutant FUS backed up these findings. FUS proteins containing ALS-linked mutations found sites of DNA damage, but then failed to bind HDAC1 and performed but a shoddy DNA repair. Some mutations were fully deficient; others exhibited less severe defects.
“FUS is an integral part of the DNA damage response pathway,” concluded Tsai. Next, she plans to examine DNA damage in other neurodegenerative diseases, and develop compounds that help neurons fix the problem.—Amber Dance.
Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, Mackenzie IR, Huang EJ, Tsai LH. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013 Sep 15. [Epub ahead of print] Abstract