Lysosomal Protein TMEM106b Is Tightly Linked to TDP-43, Tau Pathology

TMEM106b’s rap sheet is growing. Some of its genetic variants are linked to both Alzheimer’s disease and frontotemporal dementia, and fibrils of this lysosomal protein accumulate in several neurodegenerative diseases. Now, in an October 18 preprint on bioRxiv, scientists led by Jeffrey Rothstein at Johns Hopkins University School of Medicine, Baltimore, tighten the connection between TMEM106b and other pathologies. In a mouse model of amyotrophic lateral sclerosis, the authors correlated neuronal TMEM106b fibrils with loss of nuclear TDP-43, a hallmark of the disease. Similarly, in a tauopathy mouse model, the more aggregated TMEM106b a neuron had, the more phosphorylated tau it accumulated. Moving beyond mice, the authors found the same pattern in postmortem brain tissue from people who died with ALS, AD, or limbic-predominant age-related TDP-43 encephalopathy (LATE).

  • In an ALS mouse model, neuronal TMEM106b inclusions correlated with loss of nuclear TDP-43.
  • In a tauopathy mouse, TMEM106b aggregates were associated with higher p-tau.
  • TMEM106b, TDP-43, and p-tau were similarly linked in ALS and AD/LATE brains.

“These observations open the door to more in-depth investigations looking into a potential mechanistic link between TMEM106b aggregation and pathological processes in neurodegeneration,” Rothstein wrote to Alzforum. Still unknown is what comes first—do TMEM106b fibrils cause these ill effects, or vice versa?

TMEM106b variants were initially linked to ALS and FTD, both TDP-43 proteinopathies (Feb 2010 news; Aug 2012 news). Later, the gene was tied to AD (Sep 2021 news). TMEM106b aggregates have now been spotted in several neurodegenerative diseases as well as aging brain, but their pathological role remains unclear (Apr 2022 news).

Bad Company. In motor cortices from C9-ALS patients (right), neurons (green) with TMEM106b deposits (red) lose TDP-43 (light blue) from the nucleus (dark blue) compared with control cells (left). [Courtesy of Du et al., bioRxiv.]

Rather than knocking down or overexpressing TMEM106b as other mouse studies have done, Rothstein and colleagues wanted to investigate how the endogenous protein responded in the setting of TDP-43 or tau pathology. They reasoned that this would be more analogous to what happens in human disease. To investigate TDP-43 proteinopathy, joint first authors Muzi Du and Suleyman Akerman turned to a mouse model first developed by Leonard Petrucelli at the Mayo Clinic in Jacksonville, Florida (Chew et al., 2019). Du and Akerman injected an adenoviral vector carrying the C9ORF72 gene into the ventricles of newborn wild-type mice. The gene contained either two or 149 G4C2 repeats, with the longer version provoking TDP-43 pathology.

By 9 months of age, animals that received the 149-repeat version had accumulated numerous neuronal TMEM106b inclusions. Overall, about 15 percent of neurons had these deposits clustered around their nucleus. In neurons with the aggregates, TDP-43 fled the nucleus, with its nuclear/cytoplasmic ratio about a fourth lower than in control neurons (image above). In contrast, SOD1 G93A ALS mice have no TDP-43 pathology and did not accumulate TMEM106b. TMEM106b deposits are specific for TDP-43 pathology, not a general mechanism in ALS, the authors concluded.

What about tauopathies? Du and Akerman examined PS19 mice, which carry the P301S tau mutation, accumulate insoluble p-tau, and typically die around 9 months of age. At the 9-month timepoint, the intensity of neuronal p-tau staining correlated closely, at r=0.94, with TMEM106b staining. Again, the two pathologies were intimately linked within individual neurons.

The authors believe the findings are relevant to human disease. In postmortem motor cortex samples from people who died with C9-ALS, neurons with TMEM106b inclusions had a lower nuclear/cytoplasmic ratio of TDP-43 than did those without, just as in mice. Likewise, in hippocampal tissue from people with died with AD/LATE, neurons with more TMEM106b deposits had more p-tau. However, the correlation was much weaker than in mice, at r=0.29. Curiously, in hippocampal tissue from people who had AD but not LATE, TMEM106b and p-tau did not correlate.

Previous studies have linked TDP-43 pathology with a higher p-tau burden in AD (Latimer et al., 2019; Tomé et al., 2023). The findings in AD/LATE brain implicate all three pathologies together, the authors noted. “Characterizing the relationship between tau, TMEM106b, and TDP-43 in healthy and disease states will be an important step toward describing the nature of these diseases,” they wrote. In future work, they will examine whether preventing TMEM106b aggregation can slow the exodus of TDP-43 from the nucleus.—Madolyn Bowman Rogers

Comments

  1. Interesting story, if true: So far, TMEM106B fibrils have not been demonstrated in mice. Some critical controls are missing in this preprint: the current set of antibodies cannot distinguish between fibrillary/physiological (natively folded) TMEM106B. The punctate staining pattern suggests these are not fibrils but rather the properly folded TMEM106B in lysosomes. The staining pattern in human patient material looks strikingly different with mostly astrocytic TMEM106B-inclusions. The polyclonal antiserum/antibodies could also be unspecific on mouse brain tissue.

    Given the relevance and novelty of TMEM106B fibrils in mice, additional evidence should be included, e.g., by Sarkosyl extraction of fibrillary material and immunoblotting.

    The study also underscores the need for fibril-specific TMEM106B antibodies.

    View all comments by Markus Damme

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References

News Citations

  1. Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS
  2. FTD Risk Factor Confirmed, Alters Progranulin Pathways
  3. From a Million Samples, GWAS Squeezes Out Seven New Alzheimer's Spots
  4. Surprise! TMEM106b Fibrils Found in Neurodegenerative Diseases

Research Models Citations

  1. SOD1-G93A (hybrid) (G1H)
  2. Tau P301S (Line PS19)

Mutations Citations

  1. MAPT P301S

Paper Citations

  1. Chew J, Cook C, Gendron TF, Jansen-West K, Del Rosso G, Daughrity LM, Castanedes-Casey M, Kurti A, Stankowski JN, Disney MD, Rothstein JD, Dickson DW, Fryer JD, Zhang YJ, Petrucelli L. Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy. Mol Neurodegener. 2019 Feb 15;14(1):9. PubMed.
  2. Latimer CS, Burke BT, Liachko NF, Currey HN, Kilgore MD, Gibbons LE, Henriksen J, Darvas M, Domoto-Reilly K, Jayadev S, Grabowski TJ, Crane PK, Larson EB, Kraemer BC, Bird TD, Keene CD. Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort. Acta Neuropathol Commun. 2019 Jun 7;7(1):91. PubMed.
  3. Tomé SO, Tsaka G, Ronisz A, Ospitalieri S, Gawor K, Gomes LA, Otto M, von Arnim CA, Van Damme P, Van Den Bosch L, Ghebremedhin E, Laureyssen C, Sleegers K, Vandenberghe R, Rousseau F, Schymkowitz J, Thal DR. TDP-43 pathology is associated with increased tau burdens and seeding. Mol Neurodegener. 2023 Sep 30;18(1):71. PubMed.

Further Reading

Primary Papers

  1. Du M, Akerman SC, Fare C, Ruan L, Vidensky S, Mamedova L, Lee J, Rothstein JD. Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease. 2024 Oct 18 10.1101/2024.10.16.618765 (version 1) bioRxiv.

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