The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus DOI Creative Commons
Jun Yup Lee, Dylan Harney, Jonathan D. Teo

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Sept. 19, 2023

Abstract Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding biochemical changes that sensitize ageing brain to neurodegeneration will provide new opportunities prevention treatment. This study aimed determine how major genetic factors affect hippocampal proteome lipidome neurologically-normal humans over age 65. hippocampus was chosen as it is highly susceptible atrophy with in several neurodegenerative diseases. Methods Mass spectrometry-based proteomic lipidomic analysis CA1 samples 74 neurologically normal human donors, aged 66–104, used combination multiple regression models gene set enrichment identify age-dependent lipidome. ANOVA test effect alleles TMEM106B APOE genes on lipidome, adjusting age, gender, post-mortem interval. Fibrillar C-terminal fragments were isolated using sarkosyl fractionation quantified by immunoblotting. Results Forty proteins associated at false discovery rate-corrected P < 0.05, including regulate cell adhesion, cytoskeleton, amino acid lipid metabolism, ribosomal subunits. TMEM106B, a regulator lysosomal oligodendrocyte function, regulated greatest size. increase levels specific carriers rs1990622-A allele frontotemporal dementia, Alzheimer’s disease, Parkinson’s sclerosis ageing. Rs1990622-A also higher fibril content. Hippocampal lipids not significantly affected genotype, however myelin-enriched sulfatides hexosylceramides lower, polyunsaturated phospholipids higher, after controlling genotype. Conclusions Our demonstrates protein abundance increased humans, establishes predisposes formation hippocampus, provides first evidence affects homeostasis, particularly myelin lipids. data suggests one growing list glial metabolism.

Language: Английский

Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia DOI Creative Commons
Matthew Simon, Todd Logan, Sarah L. DeVos

et al.

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(4), P. 324 - 339

Published: Oct. 13, 2022

Loss-of-function heterozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified patients with frontotemporal lobar degeneration (FTLD) almost two decades ago and are generally linked to reduced PGRN protein expression levels. Although initial characterization of function primarily focused on its role extracellular signaling as a secreted protein, more recent studies revealed critical roles regulating lysosome function, including proteolysis lipid degradation, consistent lysosomal localization. Emerging from these is notion that regulates glucocerebrosidase activity via direct chaperone activities interaction prosaposin (i.e., key regulator sphingolipid-metabolizing enzymes), well anionic phospholipid bis(monoacylglycero)phosphate. This emerging biology novel promising opportunities therapeutic discovery biomarker development.

Language: Английский

Citations

56
Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration DOI
Wei Shao, Tiffany W. Todd, Yanwei Wu

et al.

Science, Journal Year: 2022, Volume and Issue: 378(6615), P. 94 - 99

Published: Oct. 6, 2022

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the

Language: Английский

Citations

49
Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging DOI
Jolien Perneel, Manuela Neumann,

Bavo Heeman

et al.

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 145(3), P. 285 - 302

Published: Dec. 17, 2022

Language: Английский

Citations

43
Generic amyloid fibrillation of TMEM106B in patient with Parkinson’s disease dementia and normal elders DOI Creative Commons
Yun Fan,

Qinyue Zhao,

Wencheng Xia

et al.

Cell Research, Journal Year: 2022, Volume and Issue: 32(6), P. 585 - 588

Published: April 27, 2022

Language: Английский

Citations

42
TAF15 amyloid filaments in frontotemporal lobar degeneration DOI Creative Commons
Stephan Tetter, Diana Arseni,

Alexey G. Murzin

et al.

Nature, Journal Year: 2023, Volume and Issue: 625(7994), P. 345 - 351

Published: Dec. 6, 2023

Abstract Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of after Alzheimer’s disease, and is often also associated with motor disorders 1 . The pathological hallmarks FTLD are neuronal inclusions specific, abnormally assembled proteins 2 In majority cases contain amyloid filament assemblies TAR DNA-binding protein 43 (TDP-43) or tau, distinct structures characterizing different subtypes 3,4 presence filaments their identities in remaining approximately 10% unknown but widely believed to be composed fused sarcoma (FUS, known as translocated liposarcoma). As such, these commonly referred FTLD–FUS. Here we used cryogenic electron microscopy (cryo-EM) determine extracted from prefrontal temporal cortices four individuals Surprisingly, found abundant FUS homologue TATA-binding protein-associated factor 15 (TAF15, 2N) rather than itself. fold formed residues 7–99 low-complexity domain (LCD) TAF15 was identical between individuals. Furthermore, same cortex brainstem two individuals, both showing upper lower neuron pathology. formation a characteristic establishes proteinopathy neurodegenerative disease. structure provides basis for development model systems well design diagnostic therapeutic tools targeting proteinopathy.

Language: Английский

Citations

27
Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments DOI
Yulong Bai, Shengnan Zhang,

Hui Dong

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(21), P. 12254 - 12311

Published: Oct. 24, 2023

Protein misfolding and aggregation, a key contributor to the progression of numerous neurodegenerative diseases, results in functional deficiencies creation harmful intermediates. Detailed visualization this process is paramount importance for improving our understanding disease mechanisms development potential therapeutic strategies. While vitro studies using purified proteins have been instrumental delivering significant insights into protein misfolding, behavior these complex milieu living cells often diverges significantly from such simplified environments. Biomedical imaging performed cell provides cellular-level information with high physiological pathological relevance, surpassing depth attainable through methods. This review highlights variety methodologies used scrutinize within biological systems. includes optical-based methods, strategies leaning on mass spectrometry, in-cell nuclear magnetic resonance, cryo-electron microscopy. Recent advancements techniques notably deepened processes features resulting misfolded species cells. The fields promises catalyze further breakthroughs comprehension interventions.

Language: Английский

Citations

26
TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes DOI Creative Commons
Yi Zeng,

Anastasiia Lovchykova,

Tetsuya Akiyama

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 22, 2024

Abstract In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from nucleus. loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that of causes widespread changes alternative polyadenylation, impacting expression disease-relevant genes (e.g., ELP1, NEFL, TMEM106B ) providing evidence polyadenylation new facet pathology.

Language: Английский

Citations

12
Spatial transcriptomic patterns underlying amyloid-β and tau pathology are associated with cognitive dysfunction in Alzheimer’s disease DOI Creative Commons
Meichen Yu, Shannon L. Risacher, Kwangsik Nho

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113691 - 113691

Published: Jan. 21, 2024

Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ pathologies than others, gene expression may play a role. We study the association between brain-wide profiles regional vulnerability (gene-to-Aβ associations) (gene-to-tau by leveraging two large independent AD cohorts. identify susceptibility genes modules co-expression network with specifically related AD. In addition, we biochemical pathways associated gene-to-Aβ gene-to-tau associations. These findings explain discordance pathologies. Finally, propose an analytic framework, linking identified gene-to-pathology associations cognitive dysfunction at individual level, suggesting potential clinical implication of

Language: Английский

Citations

10
Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis DOI Creative Commons
Peter T. Nelson, David W. Fardo, Xian Wu

et al.

Journal of Neuropathology & Experimental Neurology, Journal Year: 2024, Volume and Issue: 83(6), P. 396 - 415

Published: April 13, 2024

Abstract Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and robustly associated with dementia independent other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review literature from human studies that may shed light pathogenetic It increasingly clear certain combinations pathologic changes tend to coexist aging brains. “pure” not rare, often coexists same brains Alzheimer disease change, brain arteriolosclerosis, hippocampal sclerosis aging, and/or tau astrogliopathy (ARTAG). The patterns comorbidities provide circumstantial evidence mechanistic interactions (“synergies”) between pathologies, also suggest common upstream influences. As primary mediators vulnerability changes, genetics play key roles. Genes include TMEM106B, GRN, APOE, SORL1, ABCC9, others. anatomic distribution pathology defines condition, important cofactors for Tau pathology, endolysosomal pathways, blood-brain barrier dysfunction. A phenomenology offers insights into disease-driving mechanisms, clues diagnostic therapeutic targets.

Language: Английский

Citations

10
Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice DOI
Tuancheng Feng, Huan Du,

Cha Yang

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: March 25, 2024

Language: Английский

Citations

9