Mutant TDP-43 Deregulates AMPK Activation by PP2A in ALS Models

Nirma D Perera,Rebecca K Sheean,Malcolm K Horne,Bradley J Turner,John W Scott,Bruce E Kemp,Stefano L Sensi

doi:10.1371/journal.pone.0090449

Abstract

Bioenergetic abnormalities and metabolic dysfunction occur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models. However, whether metabolic dysfunction occurs early in ALS pathophysiology linked to different ALS genes remains unclear. Here, we investigated AMP-activated protein kinase (AMPK) activation, which is a key enzyme induced by energy depletion and metabolic stress, in neuronal cells and mouse models expressing mutant superoxide dismutase 1 (SOD1) or TAR DNA binding protein 43 (TDP-43) linked to ALS. AMPK phosphorylation was sharply increased in spinal cords of transgenic SOD1G93A mice at disease onset and accumulated in cytoplasmic granules in motor neurons, but not in pre-symptomatic mice. AMPK phosphorylation also occurred in peripheral tissues, liver and kidney, in SOD1G93A mice at disease onset, demonstrating that AMPK activation occurs late and is not restricted to motor neurons. Conversely, AMPK activity was drastically diminished in spinal cords and brains of presymptomatic and symptomatic transgenic TDP-43A315T mice and motor neuronal cells expressing different TDP-43 mutants. We show that mutant TDP-43 induction of the AMPK phosphatase, protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models. Furthermore, PP2A inhibition by okadaic acid reversed AMPK inactivation by mutant TDP-43 in neuronal cells. Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice. While AMPK activation in motor neurons correlates with progression in mutant SOD1-mediated disease, AMPK inactivation mediated by PP2A is associated with mutant TDP-43-linked ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal paralysing disorder caused by selective degeneration of upper and lower motor neurons [1,2]
AMPK activation is severely diminished in spinal cords and brains of mice and motor neuronal cells expressing mutant TAR DNA binding protein 43 (TDP-43)
Elevated AMPK activation in spinal cords of symptomatic SOD1G93A mice correlates well with key indices of energy hypermetabolism reported in this model, including increased glucose and ATP consumption [13], lactate metabolism [2], lipolysis [12] and metabolic acidosis [14]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal paralysing disorder caused by selective degeneration of upper and lower motor neurons [1,2]. The reason for the selective vulnerability of motor neurons to mutations in ubiquitously expressed proteins, such as superoxide dismutase 1 (SOD1) and TAR DNA-binding protein-43 (TDP 43), remains unclear [1,2]. Factors accounting for this selective neuronal susceptibility in ALS may include the unusual high synthetic, energetic and transport demands of large projection motor neurons [3]. This leads to high ATP consumption and mitochondrial metabolism relative to other cells, rendering these neurons susceptible to energetic defects [4]. A high-fat diet significantly delayed disease onset and increased lifespan in mutant SOD1 mice [12], while caloric restriction accelerated disease course [15,16]

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Results

Conclusion