Role of tuberin in neuronal degeneration

Abstract

One of the tuberous sclerosis complex (TSC) gene products, tuberin is assumed to be the functional component, being involved in a wide variety of cellular processes. Here, we report for the first time that tuberin dysfunction may represent a mechanism for neuronal damage in Alzheimer's disease (AD), Parkinson's disease with dementia (PD/DLB), and a mouse model of PD. Tuberin was hyperphosphorylated at Thr1462 in post-mortem frontal cortex tissue of both AD and PD/DLB patients and in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). Both PTEN and Akt phosphoactivation corresponded to the hyperphosphorylation patterns of tuberin suggesting that the PTEN-Akt pathway might be the mechanism of tuberin phosphorylation. Our data provide new information regarding the possible role of tuberin dysfunction in major neurodegenerative disorders, such as AD and PD, whereby inhibition of tuberin function may trigger an onset of neuronal cell death.

Fig. 1

Tuberin was phosphorylated at threonine 1462 via the Akt–PTEN pathway in the frontal cortex of AD and PD/DLB patients. Total cell lysates were subjected to SDS-PAGE and then immunoblotted with antibodies to p-tuberin, tuberin, p-Akt, Akt, p-PTEN, and PTEN. The blots were also probed with antibodies to PINK1 a neuronal specific marker for cortex. Separate blots with 50 μg protein were run for each set such as for p-tuberin and tuberin, p-Akt and Akt, and p-PTEN and PTEN. The blots are representative of at least three different experiments. The panel on the right shows a quantitative analysis of the blots shown in the figures. Mean ± SEM and *,** denotes P < 0.05 as compared to controls and as compared to PD respectively

Fig. 2

Tuberin was phosphorylated at threonine 1462 via the Akt–PTEN pathway in the cortex of MPTP induced acute mouse model of PD. Total cell lysates were made from frontal cortex of mice (pooled from n = 4) treated with MPTP and sacrificed at various time points (0, 4, 12, 24, 48, 72, 96 h and 1 week). These lysates were subjected to SDS-PAGE and then immunoblotted with antibodies to p-tuberin, tuberin, p-Akt, Akt, p-PTEN and PTEN. The blots were also probed with antibodies to PINK1 a neuronal specific marker for cortex. Separate blots with 50 μg protein were run for each set such as for p-tuberin and tuberin, p-AKT and AKT, and p-PTEN and PTEN. The blots are representative of at least three different experiments