The Four Stages of TDP-43 Proteinopathy

Series - Society for Neuroscience Annual Meeting 2013:

As misfolded proteins corrupt their natively folded counterparts, many neurodegenerative diseases spread from one part of the brain to the next in a predictable fashion. To take a crack at formally categorizing this sequence for the neuropathology of TDP-43, Virginia Lee of the University of Pennsylvania in Philadelphia presented a four-part staging scheme at “RNA Metabolism in Neurological Disease,” a conference held November 7-8 in San Diego. “We can add ALS to the growing list of neurodegenerative diseases where the pathology spreads in a stereotypical manner,” said Lee. Published last July, the scheme should help clinicians and researchers classify pathology at autopsy, much as Braak staging has done for Alzheimer’s disease (Brettschneider et al., 2013). That pathology progresses in a defined pattern also indicates a potential therapeutic avenue: treatments that block TDP-43 spread might freeze disease at an early stage, suggested Robert Brown of the University of Massachusetts Medical School in Worcester, who was not involved with the work.

Misfolded Aβ, tau, and α-synuclein all spread from cell to cell in the brain in predictable patterns. Might TDP-43 do the same? Studies indicate that misfolded TDP-43 infiltrates cells in culture and seeds new misfolding and aggregation (see Apr 2011 news story; Nonaka et al., 2013). To find out if brain pathology supports a cell-to-cell pathway, Johannes Brettschneider from the University of Ulm, Germany, analyzed human autopsy tissue in a study begun while he was on sabbatical in the laboratory of John Trojanowski at UPenn. Brettschneider continued the work in Ulm along with co-first author Kelly Del Tredici and co-senior author Heiko Braak.

Brettschneider examined the brains and spinal cords from 76 people who died of ALS. The researchers did not examine brains of ALS patients who died early in the disease of other causes. People with ALS typically die when their diaphragm no longer supports breathing unless they use a respirator; this can happen at different stages of disease, so the scientists believe their sample reflects various degrees of severity of ALS. They found that TDP-43 antibodies bound dash-, dot-, and skein-shaped inclusions in the cytoplasm of neurons and oligodendrocytes. Based on the patterns of these aggregates, the researchers defined four different stages.

Stage 1 cases exhibited TDP-43 aggregates only in the motor cortex, brainstem, and spinal cord. In stage 2, aggregates also dotted the prefrontal neocortex, precerebellar nuclei, and the red nucleus, a midbrain structure involved in motor control. By stage 3, TDP-43 pathology spread to the postcentral neocortex and striatum. In those few people who reached stage 4, the pathology also occurred in the temporal lobe. Overall, TDP-43 pathology appears to start in the motor cortex at the top of the brain and radiate downward to the spinal cord, as well as forward to the frontal cortices.

Since autopsy tissue provides only a static snapshot, the precise directionality of any TDP-43 transfer remains uncertain, Trojanowski said. Presumably, TDP-43 turns bad at a single point and spreads from there, Trojanowski speculated, via axons (reviewed in Braak et al., 2013).

Eleven of the people in the study had ALS due to a repeat expansion in the C9ORF72 gene. Brettschneider and colleagues noted that in those cases, the direction of spread was the same, but the density of TDP-43 lesions was greater at any given stage. This makes sense, Trojanowski said, since doctors have observed that C9ORF72 expansions create a more aggressive disease.

“It is a useful construct for understanding the [progression] of disease in the brain,” commented Brown, who called the paper “brilliant.” Even so, researchers at the meeting agreed there is more work to be done. Brown would like to see more details on TDP-43 spread in the spinal cord, because ALS is a disease primarily of spinal motor neurons, not the brain. Trojanowski said the scientists are now taking a closer look at spinal-cord pathology. They also are examining frontotemporal dementia cases to complement the ALS work, because TDP-43 proteinopathy can cause either condition or a combination of the two. That prefrontal cortex pathology was a regular feature of the ALS cases in this study could explain why cognitive dysfunction is a common symptom, the authors suggest.

Staging systems provide a useful shorthand for clinical researchers, Trojanowski said. Instead of describing dozens of places where pathology occurs, they can label a case by stage and easily communicate the extent of disease. In living persons, there is no sure way to identify stages; rather, physicians typically estimate what stage a patient is at by assessing their symptoms and deducing which brain areas are likely affected. This could prove useful if someday there are different treatments appropriate to different stages, Brown speculated.

The predictable spread of TDP-43 indicates that this misfolded protein, like others, transfers pathology down the axon and across synapses through connected neural networks. Scientists are actively working on tracing this cell-to-cell spread in animal models, as has been done already for Aβ, tau and α-synuclein (see Jul 2012 news story; Jun 2009 news story; Mougenot et al., 2011).

“The evidence of cell-to-cell spread is transformative in how we think of therapy,” Trojanowski said. An extracellular antibody to each protein might halt that spread, effectively isolating the pathology in one part of the nervous system. Scientists are already testing this new kind of passive immunotherapy in tauopathy (see Aug 2013 news story), and Trojanowski suggests a similar treatment could work for TDP-43 proteinopathy as well.—Amber Dance.

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References

News Citations

  1. Double Down: TDP-43 Fragments Bust Cells on Second Hit
  2. Aβ Sufficient for Seeding—But Is It a Prion?
  3. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?

Paper Citations

  1. Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 Jul;74(1):20-38. PubMed.
  2. Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 2013 Jul 11;4(1):124-34. PubMed.
  3. Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis--a model of corticofugal axonal spread. Nat Rev Neurol. 2013 Dec;9(12):708-14. Epub 2013 Nov 12 PubMed.
  4. Mougenot AL, Bencsik A, Nicot S, Vulin J, Morignat E, Verchère J, Bétemps D, Lakhdar L, Legastelois S, Baron TG. Transmission of prion strains in a transgenic mouse model overexpressing human A53T mutated α-synuclein. J Neuropathol Exp Neurol. 2011 May;70(5):377-85. PubMed.

Other Citations

  1. Aug 2013 news story

Further Reading

Papers

  1. Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9535-40. PubMed.
  2. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed. Correction.
  3. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy. Mol Neurobiol. 1994 Feb;8(1):25-39. PubMed.
  4. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron. 2012 Feb 23;73(4):685-97. PubMed.
  5. Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int J Exp Pathol. 1993 Oct;74(5):441-54. PubMed.
  6. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5. PubMed.
  7. Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 Jul;74(1):20-38. PubMed.
  8. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013 Sep 5;501(7465):45-51. PubMed.

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