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Administration of β-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRβ^−/− mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, β-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXRβ^−/− mice. WT mice were not affected by these doses of β-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) β and/or treatment with β-sitosterol nor were there changes in plasma levels of cholesterol or β-sitosterol. In 8-month-old LXRβ^−/− mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large …