The tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. Progress over the past 15 years has demonstrated that the TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth-factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

Figure 1

TSC2:TSC1 pathway.

Figure 2

IHC of tubers for PS6K, PS6, P4EBP1, VEGF. Tubers from TSC patients exhibit hyperactive mTOR signaling. Tuber (top panel) and epilepsy-control (bottom panel) cortical tissue was probed with antibodies recognizing the phosphorylated isoforms of S6K (A,B), S6 (C,D), 4E-BP1 (E,F), and VEGF (G,H). Large panels were taken at 5× (scale bar: 200 μm), and insets were taken at 40× (scale bar: 50 μm).