ALS: Misfolded TDP43 Appears to Spread

by Amy Madsen on Wed, 2013-06-26 16:47

In amyotrophic lateral sclerosis, abnormal clumps containing the TDP43 protein may originate in one part of brain or spinal cord and spread to other parts

Article Highlights:
  • A study of brain and spinal cord tissues taken from people with amyotrophic lateral sclerosis (ALS) suggests that the disease may spread through interconnected regions of the brain and spinal cord in a sequential pattern the investigators divided into four stages.
  • Affected areas are marked by the presence of protein clumps containing toxic TDP43 protein.
  • Spread of the toxic TDP43 protein from one region to another appears to occur by cell-to-cell transmission via nerve-cell fibers (axons).
  • If confirmed, the findings may point toward new strategies for treatments aimed at halting the spread of the disease.

A team of researchers based at institutions in the United States and Germany has described the path amyotrophic lateral sclerosis (ALS) appears to take as it progresses through different areas of the central nervous system (the brain and spinal cord).

John Trojanowski at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues, have found that from an initial starting point, hallmarks of ALS appear to spread throughout interconnected regions of the brain and spinal cord in a sequential pattern that can be divided into four stages.

Similarly to what is believed to happen in Alzheimer’s disease and Parkinson’s disease — in which disease progression can occur via transmission of toxic protein from one cell to another — ALS may spread in the brain and spinal cord via the cell-to-cell transmission of misfolded TDP43 protein, the team reports. (Protein clumps called inclusions or aggregates containing toxic TDP43 protein are present in motor neurons in all ALS, except in cases where the disease is caused by a mutation in the SOD1 gene.)

If confirmed, the findings could provide scientists with a clearer understanding of ALS disease processes and progression, and point toward new strategies for treatments designed to halt its progression.

Misfolded TDP43 appears to spread through nervous system

The research team studied postmortem tissue samples collected from 76 people with ALS between 1985 and 2012. Focusing on 22 areas of the brain and spinal cord, they examined the location and concentration of inclusions containing toxic misfolded TDP43 protein in motor neurons and other central nervous system cells (including oligodendrocytes, a type of nervous system support cell).

The investigators noted that motor neurons containing TDP43-protein-containing inclusions showed signs of degeneration, corroborating findings from previous studies that link the presence of inclusions containing TDP43 protein with the degeneration and death of motor neurons.

Based on their study, the team speculates that misfolded TDP43 protein may spread through the ALS-affected brain and spinal cord in four stages. (The four stages did not correlate with the length of time a person had ALS.)

  • Stage 1: TDP43-protein-containing inclusions appear in nerve cells in the primary motor cortex, the part of the brain involved in planning and executing voluntary movement, as well as in nerve cells in the spinal cord and brainstem involved in swallowing and breathing.
  • Stage 2: Abnormal TDP43 protein spreads forward in the brain from the primary motor cortex and into brainstem areas that are associated with balance.
  • Stage 3: TDP43 protein inclusions are found further forward in a part of the brain called the frontal cortex, which is involved in thinking and planning, and areas near the primary motor cortex that are involved with sensation.
  • Stage 4: TDP43 protein inclusions spread to the brain's temporal lobe, which is involved in visual memory, processing of sensory input, language comprehension and emotion; and the hippocampus, which is involved in moving information from short- to long-term memory and in spatial navigation.

The researchers caution that their results are preliminary and additional studies currently under way will help map TDP43 protein distribution in ALS in more detail.

Spread through axonal transport?

The underlying mechanisms controlling the spread of TDP43 protein in ALS remain unclear.

The researchers note that inclusions containing toxic TDP43 protein may initiate a process that causes normal TDP43 protein to misfold. They suggest that toxic TDP43 protein is carried from one location to another along axons — a process called axonal transport.


Study data supporting axonal transport as the mechanism underlying the spread of ALS include:

  • In stages 1 and 2, TDP43-protein-containing inclusions occur mainly in regions of the central nervous system that are closely connected by major axonal pathways.
  • In all stages, affected oligodendrocytes included only cells with close contact to axons of affected nerve cells.

The investigators say further studies in cell culture and animal models are needed to establish axonal transport as the mechanism underlying the spread of ALS within the brain and spinal cord.

For more information

The research team published its findings online May 20, 2013, in Annals of Neurology. Read the full report, for a fee: Stages of TDP43 Pathology in Amyotrophic Lateral Sclerosis.

To learn more, read Why Does ALS Spread?.

For a description of current MDA-funded research projects aimed at elucidating the role of TDP43 in ALS, see:

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