Generic amyloid fibrillation of TMEM106B in patient with Parkinson’s disease dementia and normal elders

Fan, Yun; Zhao, Qinyue; Xia, Wencheng; Tao, Youqi; Yu, Wenbo; Chen, Mingjia; Liu, Yiqi; Zhao, Jue; Yan, Siyu; Sun, Yunpeng; Si, Chenfang; Zhang, Shenqing; Zhang, Yaoyang; Li, Wensheng; Liu, Cong; Wang, Jian; Li, Dan

doi:10.1038/s41422-022-00665-3

Cited by 38 publications

(54 citation statements)

References 13 publications

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“…Insoluble TMEM106B accumulation has recently also been reported to be associated with multiple sclerosis and has been emphasized for its role in oligodendroglia [35]. It is important to note that TMEM106B filaments have been found in the brain of elderly individuals being particularly severe in individuals 75 years and older, but not present in the brain of individuals younger than 46 years of age [10, 13]. Furthermore, TMEM106B folds seem to be similar across the different diseases unlike tau filaments.…”

Section: Discussionmentioning

confidence: 99%

“…TMEM106B is a lysosomal transmembrane protein vital for lysosomal health and has been implicated as a risk factor and/or disease modulator in many neurodegenerative diseases [8]. Recently, while investigating ex-vivo filaments from individuals affected by neurodegenerative diseases, it was serendipitously discovered that TMEM106B filaments co-exist with other aggregated protein filaments in sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies [10][11][12][13]. Insoluble TMEM106B accumulation has recently also been reported to be associated with multiple sclerosis and has been emphasized for its role in oligodendroglia [35].…”

Section: Discussionmentioning

confidence: 99%

“…At the cellular level, there is evidence that this protein is present in neurons, oligodendrocytes, astrocytes and microglia [8,9]. By cryo-EM, TMEM106B filaments were recently identified in postmortem brain tissue of individuals affected by neurodegenerative diseases and of individuals with no evidence of neurodegeneration [10][11][12][13]. The TMEM106B protofilament core, spanning residues 120-254, consists of 17-19 βstrands.…”

Section: Introductionmentioning

confidence: 99%

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Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Hoq

Bharath

Hallinan

et al. 2023

Preprint

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Background: The Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. Methods: We isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. Results: We determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. Conclusions: Our findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Hoq

Bharath

Hallinan

et al. 2023

Preprint

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“…Recent advances in cryogenic electron microscopy (cryo-EM) have enabled researchers to identify the structure of fibrils extracted from postmortem brain tissue, and over the past years the structure of pathological forms of filaments formed by tau (reviewed in [ 60 ]), amyloid-β [ 31 ], α-synuclein [ 58 ], and TDP-43 [ 2 ] have been determined. Several independent cryo-EM groups now report amyloid fibrils in brain tissue of a diverse set of neurodegenerative disorders as well as older neurologically normal individuals to comprise the C-terminal domain (AA120-254/274) of transmembrane protein 106B (TMEM106B), a protein previously shown to modulate disease risk in neurodegeneration and implicated in healthy aging [ 10 , 17 , 27 , 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…Over the past months, several research groups have reported the cryo-EM structures of TMEM106B filaments derived from the brains of a variety of neurodegenerative diseases as well as older neurologically normal individuals [ 10 , 17 , 27 , 57 ]. The cryo-EM reports included fibrils obtained from sarkosyl-insoluble fractions of postmortem tissue of individuals with Alzheimer’s disease (AD), argyrophilic grain disease (AGD), amyotrophic lateral sclerosis (ALS), aging-related tau astrogliopathy (ARTAG), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), early-onset Alzheimer’s disease (EOAD), sporadic and inherited Parkinson’s disease (PD), PD dementia (PDD), inherited and sporadic frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) type A, B, C, D, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), limbic-predominant neuronal inclusion body 4R tauopathy (LNT), multiple system atrophy (MSA), pathological aging (PA), as well as neurologically normal controls (Fig.…”

Section: Introductionmentioning

confidence: 99%

Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease

Perneel

Rademakers

2022

Acta Neuropathol

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Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging. Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been closely linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal–lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Yet, the precise function of TMEM106B at the lysosomal membrane is undetermined and it remains unclear how TMEM106B modulates disease risk. Unexpectedly, several independent groups recently showed that the C-terminal domain (AA120-254) of TMEM106B forms amyloid fibrils in the brain of patients with a diverse set of neurodegenerative conditions. The recognition that TMEM106B can form amyloid fibrils and is present across neurodegenerative diseases sheds new light on TMEM106B as a central player in neurodegeneration and brain health, but also raises important new questions. In this review, we summarize current knowledge and place a decade’s worth of TMEM106B research into an exciting new perspective.

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Inflammation‐Activated Endogenous Macrophage‐Mediated Prodrug Delivery System Overcoming Biological Barriers for Enhanced Oral Meningitis Therapy

Nguyen,

et al. 2024

Adv Funct Materials

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Significant health risks are posed by meningitis due to its rapid progression, and challenges are encountered in intravenous antibiotic administration, especially in crossing the blood‐brain barrier. To address this, an inflammation‐activated, endogenous macrophage (MΦ)‐mediated oral prodrug delivery system is developed for targeted therapeutic interventions in bacterial meningitis treatment. This system is guided by inflammation‐derived chemoattractants and triggers drug release through inflammation‐induced reactive oxygen species (ROS). Comprised of naturally derived β‐glucans conjugated with the antibiotic cefotaxime (CTX) using a ROS‐responsive linker, nanoparticles (βGlus–CTX NPs) are formed in aqueous solutions. In a mouse model of Klebsiella pneumoniae‐induced meningitis, orally administered βGlus–CTX NPs are traversed by intestinal microfold cells, surpassing the intestine‐epithelial barrier, and are absorbed by resident endogenous MΦ. These MΦ‐mediated drug delivery vehicles are then traveled through the lymphatic and circulatory systems, crossing the compromised blood‐brain barrier, ultimately reaching inflamed brain tissues, guided by their derived chemoattractants. In ROS‐rich inflamed tissue environments, the linkers in the βGlus–CTX NPs are cleaved, releasing therapeutic CTX for localized treatment. Targeted antibiotic treatment for bacterial meningitis is offered by this oral, endogenous MΦ‐mediated prodrug delivery system, overcoming the robust gut‐to‐brain biological barriers and potentially enhancing effectiveness for comfortable home‐based treatment.

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Generic amyloid fibrillation of TMEM106B in patient with Parkinson’s disease dementia and normal elders

Cited by 38 publications

References 13 publications

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease

Inflammation‐Activated Endogenous Macrophage‐Mediated Prodrug Delivery System Overcoming Biological Barriers for Enhanced Oral Meningitis Therapy

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