Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

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Transcriptomic Analysis of Planarians under Simulated Microgravity or 8 g Demonstrates That Alteration of Gravity Induces Genomic and Cellular Alterations That Could Facilitate Tumoral Transformation

International Journal of Molecular Sciences ◽

10.3390/ijms20030720 ◽

2019 ◽

Vol 20 (3) ◽

pp. 720

Author(s):

Nídia de Sousa ◽

Gustavo Rodriguez-Esteban ◽

Ivan Colagè ◽

Paolo D’Ambrosio ◽

Jack van Loon ◽

...

Keyword(s):

Simulated Microgravity ◽

Model System ◽

Transcriptomic Analysis ◽

Hippo Signaling ◽

Random Positioning Machine ◽

Transcriptomic Data ◽

Earth Environment ◽

Ideal System ◽

The World ◽

Cellular Alterations

The possibility of humans to live outside of Earth on another planet has attracted the attention of numerous scientists around the world. One of the greatest difficulties is that humans cannot live in an extra-Earth environment without proper equipment. In addition, the consequences of chronic gravity alterations in human body are not known. Here, we used planarians as a model system to test how gravity fluctuations could affect complex organisms. Planarians are an ideal system, since they can regenerate any missing part and they are continuously renewing their tissues. We performed a transcriptomic analysis of animals submitted to simulated microgravity (Random Positioning Machine, RPM) (s-µg) and hypergravity (8 g), and we observed that the transcriptional levels of several genes are affected. Surprisingly, we found the major differences in the s-µg group. The results obtained in the transcriptomic analysis were validated, demonstrating that our transcriptomic data is reliable. We also found that, in a sensitive environment, as under Hippo signaling silencing, gravity fluctuations potentiate the increase in cell proliferation. Our data revealed that changes in gravity severely affect genetic transcription and that these alterations potentiate molecular disorders that could promote the development of multiple diseases such as cancer.

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Proteomic Analysis Identifies Dysfunction in Cellular Transport, Energy, and Protein Metabolism in Different Brain Regions of Atypical Frontotemporal Lobar Degeneration

Journal of Proteome Research ◽

10.1021/pr2012279 ◽

2012 ◽

Vol 11 (4) ◽

pp. 2533-2543 ◽

Cited By ~ 31

Author(s):

Daniel Martins-de-Souza ◽

Paul C. Guest ◽

David M. Mann ◽

Sigrun Roeber ◽

Hassan Rahmoune ◽

...

Keyword(s):

Protein Metabolism ◽

Proteomic Analysis ◽

Frontotemporal Lobar Degeneration ◽

Brain Regions ◽

Cellular Transport

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Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood

Developmental Brain Research ◽

10.1016/j.devbrainres.2003.10.004 ◽

2004 ◽

Vol 148 (1) ◽

pp. 43-52 ◽

Cited By ~ 57

Author(s):

Dan Qiao ◽

Frederic J. Seidler ◽

Yael Abreu-Villaça ◽

Charlotte A. Tate ◽

Mandy M. Cousins ◽

...

Keyword(s):

Brain Regions ◽

Synaptic Dysfunction ◽

Cellular Alterations

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Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz102 ◽

2019 ◽

Vol 78 (12) ◽

pp. 1124-1129

Author(s):

Jiuling Zhu ◽

Ning Wang ◽

Xianan Li ◽

Xiaojing Zheng ◽

Junli Zhao ◽

...

Keyword(s):

Cell Line ◽

Frontotemporal Lobar Degeneration ◽

Cell Model ◽

Neuroblastoma Cell ◽

Brain Regions ◽

Neuroblastoma Cell Line ◽

Null Alleles ◽

Intranuclear Inclusions ◽

A Cell

Abstract Mutations in the GRN gene coding for progranulin (PGRN) are responsible for many cases of familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP-43)-positive inclusions (FTLD-TDP). GRN mutations create null alleles resulting in decreased progranulin protein or haploinsufficiency. FTLD-TDP with GRN mutations is characterized by lentiform neuronal intranuclear inclusions that are positive for TDP-43 in affected brain regions. In this study, by stably expressed short hairpin RNA, we established a neuroblastoma cell line with decreased PGRN level. This cell line reveals TDP-43-positive intranuclear inclusions. In addition, replacement with purified PGRN protein restores normal TDP-43 nuclear distribution. This cell model can be valuable for the study of the role of PGRN in the pathogenesis in FTLD-TDP.

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A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa100 ◽

2020 ◽

Vol 79 (10) ◽

pp. 1122-1126

Author(s):

Shelley L Forrest ◽

Glenda M Halliday ◽

Anastasia Sizemova ◽

Marloes van Roijen ◽

Ciara V McGinley ◽

...

Keyword(s):

Frontotemporal Lobar Degeneration ◽

Interrater Reliability ◽

Corticobasal Degeneration ◽

Brain Regions ◽

Practical Approach ◽

Perfect Agreement ◽

Minimum Number ◽

Globular Glial Tauopathy ◽

Pick Disease ◽

Neuropathological Criteria

Abstract This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.

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Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0809-0 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 3

Author(s):

Li-Chun Lin ◽

Alissa L. Nana ◽

Mackenzie Hepker ◽

Ji-Hye Lee Hwang ◽

Stephanie E. Gaus ◽

...

Keyword(s):

Protein Aggregation ◽

Tau Protein ◽

Frontotemporal Lobar Degeneration ◽

Brain Regions ◽

Anterior Cingulate ◽

Gene Encoding ◽

Von Economo Neurons ◽

Pathogenic Variants ◽

Tau Aggregation ◽

Fork Cells

Abstract Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick’s disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

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Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration

Molecular Neurodegeneration ◽

10.1186/s13024-021-00472-1 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Swetha Mohan ◽

Paul J. Sampognaro ◽

Andrea R. Argouarch ◽

Jason C. Maynard ◽

Mackenzie Welch ◽

...

Keyword(s):

Frontotemporal Lobar Degeneration ◽

Cathepsin L ◽

Brain Regions ◽

Therapeutic Strategies ◽

Dependent Manner ◽

Loss Of Function ◽

Lysosomal Proteases ◽

Ph Dependent

Abstract Background Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints. Results In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease. Conclusions This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP-Pgrn. Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD-Pgrn and other progranulin-related diseases.

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Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?

International Journal of Molecular Sciences ◽

10.3390/ijms221910298 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10298

Author(s):

Merel O. Mol ◽

Suzanne S. M. Miedema ◽

John C. van Swieten ◽

Jeroen G. J. van Rooij ◽

Elise G. P. Dopper

Keyword(s):

Mass Spectrometry ◽

High Throughput ◽

Frontotemporal Lobar Degeneration ◽

Neurodegenerative Disorder ◽

Biological Pathways ◽

Molecular Pathways ◽

Motor Symptoms ◽

Proteomic Profiling ◽

Disease Biomarkers ◽

Cellular Alterations

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder clinically characterized by behavioral, language, and motor symptoms, with major impact on the lives of patients and their families. TDP-43 proteinopathy is the underlying neuropathological substrate in the majority of cases, referred to as FTLD-TDP. Several genetic causes have been identified, which have revealed some components of its pathophysiology. However, the exact mechanisms driving FTLD-TDP remain largely unknown, forestalling the development of therapies. Proteomic approaches, in particular high-throughput mass spectrometry, hold promise to help elucidate the pathogenic molecular and cellular alterations. In this review, we describe the main findings of the proteomic profiling studies performed on human FTLD-TDP brain tissue. Subsequently, we address the major biological pathways implicated in FTLD-TDP, by reviewing these data together with knowledge derived from genomic and transcriptomic literature. We illustrate that an integrated perspective, encompassing both proteomic, genetic, and transcriptomic discoveries, is vital to unravel core disease processes, and to enable the identification of disease biomarkers and therapeutic targets for this devastating disorder.

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Synaptic organization of the gustatory NST

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168487 ◽

1994 ◽

Vol 52 ◽

pp. 150-151

Author(s):

M. C. Whitehead

Keyword(s):

Central Nervous System ◽

Dendritic Spines ◽

Fundamental Problem ◽

Cell Types ◽

Brain Regions ◽

Excitatory Synapses ◽

Solitary Tract ◽

Synaptic Organization ◽

Synaptic Junctions ◽

Afferent Terminals

A fundamental problem in taste research is to determine how gustatory signals are processed and disseminated in the mammalian central nervous system. An important first step toward understanding information processing is the identification of cell types in the nucleus of the solitary tract (NST) and their synaptic relationships with oral primary afferent terminals. Facial and glossopharyngeal (LIX) terminals in the hamster were labelled with HRP, examined with EM, and characterized as containing moderate concentrations of medium-sized round vesicles, and engaging in asymmetrical synaptic junctions. Ultrastructurally the endings resemble excitatory synapses in other brain regions.Labelled facial afferent endings in the RC subdivision synapse almost exclusively with distal dendrites and dendritic spines of NST cells. Most synaptic relationships between the facial synapses and the dendrites are simple. However, 40% of facial endings engage in complex synaptic relationships within glomeruli containing unlabelled axon endings particularly ones termed "SP" endings. SP endings are densely packed with small, pleomorphic vesicles and synapse with both the facial endings and their postsynaptic dendrites by means of nearly symmetrical junctions.

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