In the current study, we analyzed cholesterol metabolism-associated gene expression profiles regulated by overexpressed TDP-43 using a cellular model and the amount of cholesterol in a TDP-43 overexpressed ALS mouse model and in cerebrospinal fluid of ALS patients, and we found that TDP-43 inhibited the activity of a master regulator of cholesterol biosynthesis, SREBP2, and the in vivo cholesterol level. The gene discussed is SREBF2; the disease is amyotrophic lateral sclerosis.