Axonal TDP‐43 aggregates in sporadic amyotrophic lateral sclerosis

Abstract

Aims Axonal aggregates of phosphorylated (p‐) transactive response DNA‐binding protein 43 kDa (TDP‐43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. Methods Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin‐fixed paraffin‐embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. Results (i) Aggregates of p‐TDP‐43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p‐TDP‐43 in the axons showed two characteristic microscopic features – dash‐like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p‐neurofilaments, but p‐neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p‐ and p‐independent (i)‐TDP‐43, and almost all neurones had lost their nuclear TDP‐43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP‐43‐immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p‐TDP‐43 deposition was evident. Conclusions There are two types of axonal p‐TDP‐43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p‐i‐TDP‐43 in the nuclei of postsynaptic neurones.

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

“…This study provides the first live-imaging data to support axonal-mediated spreading of TDP-43 [ 9 , 45 ]. In combination with observations obtained in cell cultures suggesting TDP-43 transfer via the axonal membrane [ 21 ], this provides evidence that axonal TDP-43 might be an important mediator of ALS/FTLD pathology.…”

Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord

“…ALS is characterized pathologically by the accumulation of ubiquitinated proteins, including TAR DNA-binding protein 43 kDa (TDP-43) ( 6 ), and this is thought to be detrimental to normal cellular function. TDP-43 pathology has been noted in upper and lower motor neuron pools, non-motor neurons, and glia of ALS patients ( 2 , 7 , 8 ), as well as within skeletal muscle ( 9 ) and axons ( 10 ). Elevated levels of TDP-43 have also been detected in the plasma of ALS patients compared with controls ( 11 ), suggesting that widespread dysregulation of RNA-binding proteins, including TDP-43, is a fundamental feature of the disease.…”

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

“…Moreover, tandem repeats of the 'prion-like' Q/N region of TDP-43, when fused to additional TDP-43, can cause aggregate formation in neuronal and non-neuronal cell lines [24]. Fifth, aggregates of phosphorylated TDP-43 (pTDP-43) are frequently present in axons of hypoglossal and facial nerves and in spinal cord anterior cells in MND, consistent with propagation of the protein [44], while FUS activity is found in granules in gray matter of the brain stem and spinal cord, which co-localise with synaptophysin [1], consistent with transport of the protein and synaptic disconnection. Sixth, stress granules are foci of cytoplasmic RNA formed in response to stress and, among many other proteins, also exhibit TDP-43 and FUS immunoreactivity [17].…”