In addition to familial ALS, abnormal aggregates of FUS are present in a portion of FTD and other neurodegenerative diseases independent of their mutations.
The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions.
Pathological FUS inclusions are found in 10% of patients with frontotemporal dementia (FTD) and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations.
Phase-separated compartments can concentrate specific RNA-binding proteins (RBPs), such as TDP-43 and fused in sarcoma (FUS), that through low-complexity, prion-like domains have an intrinsic tendency to form self-templating fibrils that are closely tied to fatal neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Previously, we engineered potentiated Hsp104 variants to suppress the proteotoxicity, aggregation, and mislocalization of FUS and other proteins that aggregate in ALS/FTD and Parkinson's disease.
FUS (fused in sarcoma) mislocalization and cytoplasmic aggregation are hallmark pathologies in FUS-related amyotrophic lateral sclerosis and frontotemporal dementia.
FTD usually belongs to the frontotemporal lobar degeneration (FTLD) disease group, and its familial forms are dominantly inherited and linked to a group of genes relevant to frontal and temporal brain pathology, such as MAPT, GRN, C9ORF72, TARDBP, CHMP2B, VCP, and FUS.
In the case of ALS and FTD, these protein aggregates are found in the cytoplasm of affected neurons and contain certain RNA-binding proteins (RBPs), namely the TAR DNA-binding protein of 43 kDa (TDP-43) and the fused in sarcoma (FUS) gene product.
We found that FUS, an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), exerted a novel feedback route to regulate circadian gene expression.
Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia.
Aggregation of fused in sarcoma (FUS) protein, and mutations in FUS gene, are causative to a range of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
Persistence of the phase-separated state and increased cytoplasmic localization are both hypothesized to predispose FUS to irreversible aggregation, which is a pathological hallmark of subtypes of amyotrophic lateral sclerosis and frontotemporal dementia.
Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs.VIDEO ABSTRACT.
Today, the AD&FTD Mutation Database provides curated, referenced information of 764 genetic variants in APP, PSEN1, and PSEN2 associated with AD and GRN, C9orf72, TBK1, MAPT, VCP, CHMP2B, TARDBP, and FUS associated with FTD and related diseases.
Intriguingly, many of the RNA targets of TDP-43 and FUS are involved in synaptic transmission and plasticity, indicating that synaptic dysfunction could be an early event contributing to motor and cognitive deficits in ALS and FTD.
ALS-associated FUS-NLS mutations weaken the chaperone activity of Transportin and loss of FUS arginine methylation, as seen in FTD-FUS, promote phase separation, and stress granule partitioning of FUS.
We discuss how TDP-43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.
A significant increase of Fe deposition was observed in the claustrum, caudate nucleus, globus pallidus, thalamus, and subthalamic nucleus of the FTLD-FUS and FTLD-TDP groups, while in the ALS one, the Fe increase was only observed in the caudate and the subthalamic nuclei.
These data suggest that cytoplasmic FUS aggregates impair dendritic mRNA trafficking and translation, in turn leading to dendritic homeostasis disruption and the development of FTD phenotypes.
Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS.