Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Fang, Yuting; Tsai, Kuen‐Jer; Chang, Yu‐Hsu; Kao, Patricia F.; Woods, Rima; Kuo, Pan Hsien; Wu, Cheng-Chun; Liao, Jhih Ying; Chou, Shih Chieh; Lin, Vinson; Jin, Lee Way; Yuan, Hanna S.; Cheng, Irene H.; Tu, Pang‐Hsien; Chen, Yun‐Ru

doi:10.1038/ncomms5824

Cited by 168 publications

(255 citation statements)

References 56 publications

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“…Despite the emphasis on the unstructured nature of IDRs, it has been proposed that transient, partially populated folded conformations, facilitated by particular amino acid stretches, may be disrupted by mutations, for instance, in TDP-43 (Conicella et al 2016). TDP-43 fibrilization is thought to seed aggregates of itself (Furukawa et al 2011) and crossseed aggregations of other proteins (Fang et al 2014).…”

Section: Rbps and Membraneless Organellesmentioning

confidence: 99%

“…RNA transport granules are another important class of membrane-less organelles with specific neuronal relevance in localized mRNA expression (Kiebler and Bassell 2006). Their ability to fuse into droplet states has become of great interest for disease because the properties driving this protective aggregation, which can involve phase transitions of mutant FUS and TDP-43, can also lead to amyloid-like states (Fang et al 2014;Murakami et al 2015). This can be imagined as a transition from liquid droplets to hydrogels to irreversible amyloid fibers, giving rise to a gradient in rigidity (Fig.…”

Section: Rbps and Membraneless Organellesmentioning

confidence: 99%

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RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Rbps and Membraneless Organellesmentioning

confidence: 99%

Section: Rbps and Membraneless Organellesmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…Similarly, toxic soluble oligomers and cytoplasmic inclusions of TDP-43 or FUS are associated with ALS and frontotemporal dementia (13)(14)(15)(16)(17)(18)(19)(20). These misfolded protein conformers are recalcitrant and represent a colossal roadblock in the treatment of these diseases.…”

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confidence: 99%

Mechanistic Insights into Hsp104 Potentiation

Torrente¹,

Chuang

Noll³

et al. 2016

Journal of Biological Chemistry

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Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve protein aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2-3 subunits of the Hsp104 hexamer must bear an A503V potentiating mutation to elicit enhanced disaggregase activity in the absence of Hsp70. We also define the ATPase and substratebinding modalities needed for potentiated Hsp104 A503V activity in vitro and in vivo. Hsp104 A503V disaggregase activity is strongly inhibited by the Y257A mutation that disrupts substrate binding to the nucleotide-binding domain 1 (NBD1) pore loop and is abolished by the Y662A mutation that disrupts substrate binding to the NBD2 pore loop. A503V displays a more robust activity that is unperturbed by sensor-1 mutations that greatly reduce Hsp104 activity in vivo. Indeed, ATPase activity at NBD1 or NBD2 is sufficient for Hsp104 potentiation. Our findings will empower design of ameliorated therapeutic disaggregases for various neurodegenerative diseases.Protein misfolding and aggregation are associated with a wide variety of diseases, ranging from type II diabetes (1, 2) to neurodegenerative diseases, such as fatal familial insomnia (3, 4), Parkinson disease, and amyotrophic lateral sclerosis (ALS) (5-7). In Parkinson disease patients, ␣-synuclein (␣-syn) 6 forms toxic soluble oligomers as well as amyloid structures that accumulate in Lewy bodies and contribute to the death of dopaminergic neurons (8 -12). Similarly, toxic soluble oligomers and cytoplasmic inclusions of TDP-43 or FUS are associated with ALS and frontotemporal dementia (13-20). These misfolded protein conformers are recalcitrant and represent a colossal roadblock in the treatment of these diseases.Hsp104 is a 102-kDa AAAϩ ATPase (21) from Saccharomyces cerevisiae capable of dissolving disordered protein aggregates as well as dismantling amyloid fibrils and toxic soluble oligomers (22-33). It assembles into a homohexameric barrel structure with a central channel (34 -39). Hsp104 processes protein aggregates by directly translocating substrates either partially or completely through this channel (35, 36, 40 -46). Hsp104 encompasses an N-terminal domain, two nucleotidebinding domains (NBD1 and NBD2), a coiled-coil middle domain (MD), and a C-terminal domain important for oligomerization (Fig. 1A) (47). Both NBDs contain Walker A and Walker B motifs that are critical for nucleotide binding and hydrolysis, respectively (48). ATP hydrolysis takes place primarily at NBD1, whereas NBD2 has a nucleotide-dependent oligomerization function (29, 34, 49 -52).Remarkably, Hsp104 can remodel amyloid substrates alone, without the aid of any other chaperones (22,24,26,31,33,45,(53)(54)(55)(56). However, to disaggregate amorphous protein aggregates, Hsp104 usually needs to collaborate with the Hsp110, Hsp70, and Hsp40 chaperone system (23,26,30,32,57). Moreover, small heat shock proteins...

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“…Transactive response DNA binding protein 43 kDa (TDP-43) is the major component of inclusions in patients with frontotemporal lobar degeneration (FTD) and amyotrophic lateral sclerosis (ALS) [31][32][33][34], which are ubiquitin-positive intracytoplasmic deposits in nerve and glial cells causing pathological conditions in these patients. We hypothesized that Dimebon's protective properties might be attributed to inhibition of aggregate formation.…”

Section: Dimebon Inhibits Formation Of Transactivementioning

confidence: 99%

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

2015

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Dimebon (latrepirdine) is an anti-histaminergic agent which belongs to a fast-growing group of "old" medicines suggested to be of therapeutic utility for pathological conditions different from their original design ("repositioning"). Here, we overview the most recent studies on Dimebon directed to pathological processes in the brain-involving in vivo models of proteinopathies. In the latter, neurodegenerative effects are attributed to a group of aggregate-prone proteins such as γ-synuclein, hyperphosphorylated tau, and fused in sarcoma (FUS), which are engaged in numerous neurological diseases. We also focus on in vitro models comprised of cultured SH-SY5Y neuroblastoma cells expressing mutant forms of transactive response DNA binding protein 43 kDa (TDP-43) and showing a reduced number of TDP-43 inclusion-containing cells upon Dimebon treatment along with activation of autophagy markers. Finally, we discuss Dimebon's action in improving cellular energy balance, stabilizing mitochondrial function by increasing the threshold for nonselective mitochondrial pore opening, as well as increasing the calcium retention capacity of mitochondria and reducing lipid peroxidation. Our results, together with data from other laboratories, warrant re-evaluation of the therapeutic potential of Dimebon and its newly designed analogs as promising disease-modifying agents to treat neurodegenerative disorders. Further, emerging data favor a possible anti-aging effect and application of Dimebon for the treatment of depression, anxiety, and ischemia. The most pronounced effect of Dimebon is observed when treatment starts early in disease onset. This is a major factor which needs to be taken into account when planning future clinical trials.

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Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Cited by 168 publications

References 56 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Mechanistic Insights into Hsp104 Potentiation

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

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