Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43

Jiang, Yi; Cao, Qing; Sawaya, M.R.; Abskharon, Romany; Ge, P.; DeTure, Michael; Dickson, Dennis W.; Fu, Janine; Loo, Rachel R. Ogorzalek; Loo, Joseph A.; Eisenberg, David S.

doi:10.1038/s41586-022-04670-9

Cited by 86 publications

(75 citation statements)

References 49 publications

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“…Presence of TDP‐43 filaments in sarkosyl‐insoluble preparations has been a matter of discussion; however, Arseni et al . have shown the presence and structure of TDP‐43 filaments in ALS with FTLD [6, 42]. Phosphorylation may be relevant to the conformation of TDP‐43 in pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (GRN) vs Type B (C9orf72)

Cracco

Doud

Hallinan

et al. 2022

Neuropathology Appl Neurobio

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Aims: Frontotemporal dementias are neuropathologically characterised by frontotemporal lobar degeneration (FTLD). Intraneuronal inclusions of transactive response DNAbinding protein 43 kDa (TDP-43) are the defining pathological hallmark of approximately half of the FTLD cases, being referred to as FTLD-TDP. The classification of FTLD-TDP into five subtypes (Type A to Type E) is based on pathologic phenotypes; however, the molecular determinants underpinning the phenotypic heterogeneity of FTLD-TDP are not well known. It is currently undetermined whether TDP-43 post-translational modifications (PTMs) may be related to the phenotypic diversity of the FTLDs. Thus, the investigation of FTLD-TDP Type A and Type B, associated with GRN and C9orf72 mutations, becomes essential. Methods: Immunohistochemistry was used to identify and map the intraneuronal inclusions. Sarkosyl-insoluble TDP-43 was extracted from brains of GRN and C9orf72 mutation carriers post-mortem and studied by Western blot analysis, immuno-electron microscopy and mass spectrometry. Results: Filaments of TDP-43 were present in all FTLD-TDP preparations. PTM profiling identified multiple phosphorylated, N-terminal acetylated or otherwise modified residues, several of which have been identified for the first time as related to sarkosylinsoluble TDP-43. Several PTMs were specific for either Type A or Type B, while others were identified in both types. Conclusions: The current results provide evidence that the intraneuronal inclusions in the two genetic diseases contain TDP-43 filaments. The discovery of novel, potentially type-specific TDP-43 PTMs emphasises the need to determine the mechanisms leading to filament formation and PTMs, and the necessity of exploring the validity and occupancy of PTMs in a prognostic/diagnostic setting.

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Section: Discussionmentioning

confidence: 99%

Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (GRN) vs Type B (C9orf72)

Cracco

Doud

Hallinan

et al. 2022

Neuropathology Appl Neurobio

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“…Therefore, specific reduction of TMEM106B in C9ORF72 -RE+ve samples may be a compensatory attempt to regulate lysosomal function, or a concomitant loss of lysosomal proteins due to C9ORF72 -RE-dependent lysosomal dysfunction. Alternatively, lower synaptic expression of TMEM106B may be due to mislocalisation and aggregation in other neuronal compartments, as recently shown in FTLD-TDP [116]. Finally, TMEM106B knockdown leads to altered lysosomal trafficking and reduced dendritic arborisation [117], so a loss of TMEM106B at the synapse may drive vulnerability.…”

Section: Discussionmentioning

confidence: 99%

Synaptic proteomics reveal distinct molecular signatures of cognitive change andC9ORF72repeat expansion in the human ALS cortex

László

Hindley

Avila

et al. 2022

Preprint

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The two major hypotheses of Amyotrophic Lateral Sclerosis (ALS) pathogenesis (dying-forward and dying-back) have synapses at their core. Furthermore, increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in ALS. Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins at the synapse, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS synapses, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synapses, highlighting novel synaptic proteins that may underlie the synaptic vulnerability in these patients. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE+ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition.

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“…5): (I) the fibrils form within the lumen and potentially later escape the lysosome, or (II) the fibrils can only form within the cytosol once the C-terminal domain is released from the lumen. In this regard, Jiang et al remarked that the presence of negatively charged amino acids directed at each other suggests that the fibrils can only form in an acidic environment, where the negative This may potentially also occur by SPPL2a, similar to non-canonical shedding of TNF-α [62] charges are attenuated, as would be the case in the acidic lumen of the lysosome [27].…”

Section: Fibril Formationmentioning

confidence: 99%

“…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%

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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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Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43

Cited by 86 publications

References 49 publications

Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (GRN) vs Type B (C9orf72)

Distinguishing post‐translational modifications in dominantly inherited frontotemporal dementias: FTLD‐TDP Type A (GRN) vs Type B (C9orf72)

Synaptic proteomics reveal distinct molecular signatures of cognitive change andC9ORF72repeat expansion in the human ALS cortex

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

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