TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy

Edwards, George A.; Wood, Caleb A.; He, Yang; Nguyen, Quynh; Kim, Peter J.; Gomez-Gutierrez, Ruben; Park, Kyung-Won; Xu, Yong; Zurhellen, Cody; Al-Ramahi, Ismael; Jankowsky, Joanna L.

doi:10.1007/s00401-024-02701-5

Cited by 5 publications

(3 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lysosomal dysfunction is commonly observed during ageing and in neurodegenerative diseases [ 10 ] and it has been suggested that this may be a consequence of TMEM106B aggregation [ 24 ], although it is also possible that lysosomal dysfunction leads to TMEM106B aggregation. Interestingly, loss of TMEM106B has been shown to exacerbate TDP-43 and tau pathologies, as well as neurodegeneration in transgenic mice [ 13 , 15 , 17 , 44 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Bacioglu,

Schweighauser,

Gray

et al. 2024

acta neuropathol commun

View full text Add to dashboard Cite

Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.

show abstract

Section: Discussionmentioning

confidence: 99%

Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Bacioglu,

Schweighauser,

Gray

et al. 2024

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Intriguingly, recent two in vivo studies investigated the role of TMEM106B in tau P301S transgenic mouse model. Feng et al show that loss of TMEM106B enhances the accumulation of pathological tau and results in severe neuronal loss, especially in the neuronal soma in the hippocampus [ 52 ]. The other found similar results that TMEM106B deletion accelerates cognitive decline and tau pathology in tau P301S mice.…”

Section: Multiple Single Nucleotide Polymorphisms (Snps) Of Tmem106bmentioning

confidence: 99%

Physiological and pathological functions of TMEM106B in neurodegenerative diseases

Zhu,

Zhang,

Meng

et al. 2024

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

As an integral lysosomal transmembrane protein, transmembrane protein 106B (TMEM106B) regulates several aspects of lysosomal function and is associated with neurodegenerative diseases. The TMEM106B gene mutations lead to lysosomal dysfunction and accelerate the pathological progression of Neurodegenerative diseases. Yet, the precise mechanism of TMEM106B in Neurodegenerative diseases remains unclear. Recently, different research teams discovered that TMEM106B is an amyloid protein and the C-terminal domain of TMEM106B forms amyloid fibrils in various Neurodegenerative diseases and normally elderly individuals. In this review, we discussed the physiological functions of TMEM106B. We also included TMEM106B gene mutations that cause neurodegenerative diseases. Finally, we summarized the identification and cryo-electronic microscopic structure of TMEM106B fibrils, and discussed the promising therapeutic strategies aimed at TMEM106B fibrils and the future directions for TMEM106B research in neurodegenerative diseases.

show abstract

“…TMEM106B pathology co-occurs with tau pathology in PSP, PD, FTLD-tau, and AD [12][13][14][15][16]. In addition, TMEM106B mutation or loss of function can influence tau pathology in transgenic mice [59,60]. Our previous studies using forward genetic screens to isolate suppressors of tau pathology in tau Tg C. elegans have revealed a number of modifier genes, including spop-1, sut-2, and sut-6 [43,44,49,[61][62][63][64].…”

Section: Interactions Of Tmem With Common Suppressors Of Tau Pathologymentioning

confidence: 99%

TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy

Riordan,

Saxton,

McMillan

et al. 2024

Preprint

View full text Add to dashboard Cite

Genetic variation in the lysosomal and transmembrane protein 106B (TMEM106B) modifies risk for a diverse range of neurodegenerative disorders, especially frontotemporal lobar degeneration (FTLD) with progranulin (PGRN) haplo-insufficiency, although the molecular mechanisms involved are not yet understood. Through advances in cryo-electron microscopy (cryo-EM), homotypic aggregates of the C-Terminal domain of TMEM106B (TMEM CT) were discovered as a previously unidentified cytosolic proteinopathy in the brains of FTLD, Alzheimer’s disease, progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) patients. While it remains unknown what role TMEM CT aggregation plays in neuronal loss, its presence across a range of aging related dementia disorders indicates involvement in multi-proteinopathy driven neurodegeneration. To determine the TMEM CT aggregation propensity and neurodegenerative potential, we characterized a novel transgenicC. elegansmodel expressing the human TMEM CT fragment constituting the fibrillar core seen in FTLD cases. We found that pan-neuronal expression of human TMEM CT inC. eleganscauses neuronal dysfunction as evidenced by behavioral analysis. Cytosolic aggregation of TMEM CT proteins accompanied the behavioral dysfunction driving neurodegeneration, as illustrated by loss of GABAergic neurons. To investigate the molecular mechanisms driving TMEM106B proteinopathy, we explored the impact of PGRN loss on the neurodegenerative effect of TMEM CT expression. To this end, we generated TMEM CT expressingC. eleganswith loss ofpgrn-1, theC. elegansortholog of human PGRN. Neither full nor partial loss ofpgrn-1altered the motor phenotype of our TMEM CT model suggesting TMEM CT aggregation occurs downstream of PGRN loss of function. We also tested the ability of genetic suppressors of tauopathy to rescue TMEM CT pathology. We found that genetic knockout ofspop-1, sut-2,andsut-6resulted in weak to no rescue of proteinopathy phenotypes, indicating that the mechanistic drivers of TMEM106B proteinopathy may be distinct from tauopathy. Taken together, our data demonstrate that TMEM CT aggregation can kill neurons. Further, expression of TMEM CT inC. elegansneurons provides a useful model for the functional characterization of TMEM106B proteinopathy in neurodegenerative disease.

show abstract

TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy

Cited by 5 publications

References 55 publications

Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Physiological and pathological functions of TMEM106B in neurodegenerative diseases

TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy

Contact Info

Product

Resources

About