The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.
The Tar DNA-Binding Protein 43 (TDP-43) and its phosphorylated isoform (pTDP-43) are the major components associated with ubiquitin positive/Tau-negative inclusions found in neurons and glial cells of patients suffering of amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration-TDP-43 (FTLD-TDP).
Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration.
Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
More than half of the patients with Alzheimer's disease (AD) have comorbidities including TDP-43 and Lewy bodies, which are also associated with frontotemporal lobar degeneration and dementia with Lewy bodies, respectively.
This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum.
The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions.
Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models.
When inhibited by siRNA or some by submicromolar concentrations of small-molecule inhibitors, 33 genes of the druggable genome increased progranulin levels in mouse primary cortical neurons; several of these also raised progranulin levels in FTLD model mouse neurons.
Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS.
<b>Objective:</b> To investigate associations between peripheral innate immune activation and frontotemporal lobar degeneration (FTLD) in progranulin gene (<i>GRN</i>) haploinsufficiency.
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS).
FTD syndromes are characterized by lobar atrophy (frontotemporal lobar degeneration or FTLD) and the presence of either cellular TDP43 (FTLD-TDP), tau (FTLD-tau), or FUS aggregates, while extracellular β-amyloid plaques and hyperphosphorylated tau tangles develop in AD.
Induced pluripotent stem cells (iPSCs) were generated from peripheral blood-derived erythroid progenitor cells obtained from a presymptomatic female carrying the heterozygous R418Xprogranulin (GRN) nonsense mutation, known to cause autosomal dominant frontotemporal lobar degeneration.
Brain sections from 5 PPA participants with postmortem diagnoses of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) were immunohistochemically stained using an antibody to phosphorylated TDP-43 and quantitatively examined for regional and hemispheric distribution using unbiased stereology.
Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein.
However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups.
This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA-binding protein 43 or FET protein accumulation (FTLD-tau, FTLD-TDP and FTLD-FET respectively).
TAR DNA-binding protein 43 (TDP-43) is a hallmark of some neurodegenerative disorders, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion.