23 May2008. Also known as motor neuron disease, amyotrophic lateral sclerosis is a progressive, fatal neurodegenerative disorder that has traditionally been defined by World Federation of Neurology criteria (El Escorial) as a disease of the upper and lower motor neurons. But is it time to redefine it? As outlined in two recent papers, ALS pathology is found far and wide, turning up in tissue such as the neocortex, nigrostriatal system, and the cerebellum. “Both papers show that ALS is not just a disease of upper and lower motor neurons,” John Trojanowski, a principal author on one of the papers, told ARF. When taken with new mouse model data suggesting that the onset of some forms of ALS is accelerated by non-neuronal cells (see ARF companion news story), evidence seems to be growing that ALS is a multi-cell, multisystem disorder. “It is important to be aware of that as you conceptualize therapy,” said Trojanowski.

In the May Archives of Neurology, Trojanowski, Virginia Lee, and colleagues at the University of Pennsylvania report that ALS patients have aggregates of TDP-43 in many areas of their brain. These researchers were the first to identify TDP-43, or transactivating responsive sequence DNA-binding protein of 43 kDa, as a major component of inclusion bodies in ALS and in frontotemporal lobar degeneration with ubiquitin-positive inclusions (see ARF related news story). Since then, the link between the protein (also known as TARDP) and ALS has strengthened. TDP-43 inclusions seem to define sporadic ALS and many familial ALS cases (see ARF related news story and ARF news story), distinguishing them from the small fraction of patients with SOD1 mutations (see McKenzie et al., 2007).The new TDP-43 evidence seems to suggest there is more to ALS than motor neurons.

First author Felix Geser and colleagues compared TDP-43 pathology in postmortem brain tissue from a cohort of 31 ALS patients with that in eight controls. In keeping with the ubiquitous expression of the protein, the researchers found cellular TDP-43 inclusions were widespread in the brain, including in the thalamus, cingulate gyrus, frontal, temporal, parietal and occipital lobes; hippocampus, and amygdala. Control subjects had no TDP-43 inclusions in their brains.

These findings are echoed in a report from Hitoshi Takahashi and colleagues at the University of Niigata, Japan. Writing in Acta Neuropathologica online, first author Yasushi Nishihira and colleagues characterize TDP-43 pathology in 35 sporadic ALS patients. In all cases, the researchers found protein inclusions, both neuronal and glial, in many regions of the brain, including the neocortex, hippocampus, the nigrostriatal system, and amygdala. Nishihira and colleagues suggest there are two different pathological patterns. Type 2 patients are distinguishable from type 1 patients in having inclusions in the frontotemporal cortex, hippocampal formation, neostriatum, and substantia nigra. In type 1, pathology is found in midbrain motor cortex non-motor neurons. The researchers found that in type 2 patients, neuronal loss was evident in non-motor neurons, such as in the neocortex or hippocampus. Type 2 ALS also associates with dementia, suggesting that TDP-43 inclusions in areas of the brain that are required for learning and memory may be causative for cognitive decline. Trojanowski’s group made a similar observation. Although they had only five cases with ALS-dementia—too small a sample for accurate statistical analysis—Geser and colleagues found that TDP-43 pathology was more severe in the hippocampus and neocortex in those patients with dementia.

Trojanowski suggested that TDP-43 is causing a sea change in thought about ALS. Going back 50 years, ALS literature has documented clinical manifestations in patients other than upper and lower motor neuron disease, which Escorial criteria have always defined as an ALS-Plus syndrome rather than true ALS. “I’m not implying that we are the first to conceive of ALS as a disease affecting parts of the nervous system beyond the upper and lower motor neurons,” said Trojanowski, “but I think TDP-43 is redefining ALS in a completely new way that will be important for therapy. It should, it will, and it has stimulated efforts to ascertain clinical deficits in these other systems beyond pyramidal motor system,” he said.—Tom Fagan


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News Citations

  1. Research Brief: Redefining ALS—SOD Work Lays New Ground
  2. New Ubiquitinated Inclusion Body Protein Identified
  3. Gene Mutations Place TDP-43 on Front Burner of ALS Research
  4. Heady Times for Researchers Studying TDP-43

Paper Citations

  1. . El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and th. J Neurol Sci. 1994 Jul;124 Suppl:96-107. PubMed.
  2. . Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007 May;61(5):427-34. PubMed.

Further Reading

Primary Papers

  1. . Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol. 2008 May;65(5):636-41. PubMed.
  2. . Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol. 2008 Aug;116(2):169-82. PubMed.