Concept: Frontotemporal dementia
The aim of the present work is to extensively evaluate the pharmaceutical attributes of currently available riluzole presentations. The article describes the limitations and risks associated with the administration of crushed tablets, including the potential for inaccurate dosing and reduced rate of absorption when riluzole is administered with high-fat foods, and the advantages that a recently approved innovative oral liquid form of riluzole confers on amyotrophic lateral sclerosis (ALS) patients. The article further evaluates the patented and innovative controlled flocculation technology used in the pseudoplastic suspension formulation to reduce the oral anesthesia seen with crushed tablets, resulting in optimized drug delivery for riluzole. Riluzole is the only drug licensed for treating ALS, which is the most common form of motor neurone disease and a highly devastating neurodegenerative condition. The licensed indication is to extend life or the time to mechanical ventilation. Until recently, riluzole was only available as an oral tablet dosage form in the UK; however, an innovative oral liquid form, Teglutik(®) 5 mg/mL oral suspension, is now available. An oral liquid formulation provides an important therapeutic option for patients with ALS, >80% of who may become unable to swallow solid oral dosage forms due to disease-related dysphagia. Prior to the launch of riluzole oral suspension, the only way for many patients to continue to take riluzole as their disease progressed was through crushed tablets. A novel suspension formulation enables more accurate dosing and consistent ongoing administration of riluzole. There are clear and important advantages such as enhanced patient compliance compared with crushed tablets administered with food or via an enteral feeding tube and the potential for an improved therapeutic outcome and enhanced quality of life for ALS patients.
Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood.
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a Rab1a effector, C9orf72 controls initiation of autophagy by regulating the Rab1a-dependent trafficking of the ULK1 autophagy initiation complex to the phagophore. Accordingly, reduction of C9orf72 expression in cell lines and primary neurons attenuated autophagy and caused accumulation of p62-positive puncta reminiscent of the p62 pathology observed in C9ALS/FTD patients. Finally, basal levels of autophagy were markedly reduced in C9ALS/FTD patient-derived iNeurons. Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.
Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is one of the most common pathological findings associated with the clinical FTLD syndromes. However, molecular characterization with genetic sequencing and protein expression techniques are recognizing many new subtypes for FTLDs. FTLDs are diverse and new nomenclature schemes have been proposed based on the molecular defects that are being discovered ( Mackenzie et al., 2010 , Acta Neuropathologica, 119, 1). Adult polyglucosan body disease (APBD) is a very rare disorder associated with systemic neurological signs and symptoms including progressive dementia with executive dysfunction and motor neuron disease. We report the clinical course of an individual with a clinical FTLD and the as yet unreported findings of coexistent APBD with FTLD-U and transactivation response DNA-binding protein-43 (TDP-43)-positive inclusions at autopsy (or more accurately, FTLD-TDP). It is unclear if these distinct findings are coincidental in this individual, or if pathogenic pathways may intersect to promote these coexisting pathologies.
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 3 years ago
Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.
Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
The terms frontotemporal lobar degeneration (FTLD) indicate a large set of neurodegenerative diseases, heterogeneous in their genetic, pathologic and clinical aspects.
TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.
Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.