‘Fibril TMEM106B new finding for the research field’

Three research groups independently found the fibril TMEM106B in brains of patients with neurodegenerative disease, including frontotemporal dementia (FTD). “This is a new finding for the research field”, says doctor-researcher MPE (Marie-Paule) van Engelen of the Alzheimer Center in Amsterdam.

In US research, amyloid fibrils were extracted from brains of 4 patients with 4 out of 5 subclasses of the FTD-TDP subtype.¹ That subtype is characterized by certain clinical signs and pathological neural inclusions with immunoreactivity of TDP-43 (TAR DNA-binding protein). Instead of fibrils from the protein TDP-43, the researchers found fibrils with a fragment of the transmembrane protein 106B (TMEM106B). That is a lysosomal protein that was previously thought to be a genetic risk factor for FTD-TDP. In addition, the researchers did find high concentrations of aggregated TDP-43 protein in a non-fibrillar form using immunogold labelling. The findings confirm that FTD-TDP is associated with amyloid fibrils, but these are formed by TMEM106B and not TDP-43.

Age dependent

Another international study (England, USA, Japan) examined the structure of TMEM106B fibrils from brain regions of 22 patients with high amyloid accumulations and 3 subjects with little or no amyloid.² Three different ways of folding of TMEM106B were found, with no clear relationship with the disease. TMEM106B fibrils were also found in the brains of healthy elderly subjects. According to the researchers, this indicates that the formation of the fibrils is age-dependent.

The third study, with researchers from the US, Canada and Belgium, demonstrated TMEM106B in brain tissue from deceased patients with TDP-43 pathology, progressive supranuclear palsy or ‘Lewy body’ dementia.³ According to the researchers, the fact that TMEM106B is found in high concentrations indicates that there should be more focus on this protein and its possible relationship with the development or acceleration of various neurodegenerative diseases.

References

1. Jiang YX, Cao O, Sawaya MR, et al. Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature. 2022;605:304-9.
2. Schweighauser M, Arseni D, Bacioglu M, et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature. 2022;605:310-4.
3. Chang A, XiangX, Wang J, et al. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. 2022;185:1346-55.

Comments doctor-researcher/PhD student Marie-Paule van Engelen, Alzheimer Center Amsterdam

“It is noteworthy that 3 research groups independently found the TMEM106B fibril in brains of patients with neurodegenerative diseases, including FTD caused by TDP-43 pathology. Contrary to expectations, the research groups found TMEM106B fibrils instead of TDP-43 fibrils. The TMEM106B fibrils are a new finding in the research field. Most previous studies have used ‘N-terminal’ antibodies to label the protein. But in TMEM106B, the ‘C-terminal’ turns the protein into fibrils. That may explain why these aggregates have gone undetected for so long.”

Place in perspective

“These interesting findings raise more questions than they answer. The most important thing is to find out if and how TMEM106B fibrils contribute to the pathology in neurodegenerative diseases and whether there is a specific relationship with TDP-43. Are these fibrils toxic on their own, or do they stimulate the aggregation of other proteins, such as TDP-43. What triggers the formation of the fibrils? These are all questions that remain unanswered for now, but need to be explored in the future. What is also remarkable is that the TMEM106B fibrils have also been found in healthy, older people. This may mean that TMEM106B fibrils occur in ‘normal’ aging as well as in neurodegenerative diseases. It is important to further investigate the possible harmfulness of the fibril in order to put the current findings in perspective.”

Specific FTD Biomarkers

“We conduct our own research into the protein TDP-43, which occurs in approximately half of the patients with FTD. My PhD research focuses on improving the diagnosis of FTD. Our goal is to find specific biomarkers for FTD that can be detected early in the disease process. We analyze cerebrospinal fluid from living patients to detect TDP-43. Previous FTD research has linked the gene encoding TMEM106B to FTD, involving genetic variation in the TMEM106Blocus has been identified as a risk factor for FTD caused by TDP-43 inclusions. This is especially true for patients with the GRN-mutation.”

“Once again it appears that the processes behind the development of FTD are very complex. If we better understand how everything works and how everything is connected, we may be able to develop targeted medication, but more fundamental research is needed first.”