Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons.

Marcus S. Dyer,Adele Woodhouse,Catherine A. Blizzard

doi:10.3390/brainsci11070883

Abstract

Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliest detectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigated how mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracycline inducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannot enter the nucleus (TDP-43ΔNLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH mice to visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WT and controls, TDP-43ΔNLS drove a robust loss in spine density in all the dendrite regions of the upper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in the generation of network dysfunction in ALS likely through impacting the formation or durability of excitatory synapses. These findings are relevant to the vast majority of ALS cases, and provides further evidence that upper motor neurons may need to be protected from TDP-43 mediated synaptic excitatory changes early in disease.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron disease
Whilst how neuronal dysfunction arises in ALS is not known, it is becoming apparent that upper motor neuron dysfunction is a critical factor in ALS [2]
We investigated the role of mislocalised TDP-43 at the dendritic spine by employing an inducible model, in which TDP-43 that cannot enter the nucleus is expressed in layer V pyramidal neurons within the motor cortex; crossed with the Thy-1 YFP-H mouse to visualize dendritic spines

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is the most common form of motor neuron disease. ALS involves the progressive loss of upper motor neurons in the motor cortex and lower motor neurons in the spinal cord. This leads to muscle weakness, muscle loss and eventually death in 3–5 years for most patients [2]. ALS is clinically heterogenous, a heterogeneity which can be effectively correlated to degree of upper and lower motor neuron burden [3,4]. Insufficient understanding of the cause of ALS or how pathology progresses through the neuromotor system has hampered the development of effective therapeutics

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