Review: Prion‐like mechanisms of transactive response DNA binding protein of 43 kDa (<scp>TDP</scp>‐43) in amyotrophic lateral sclerosis (<scp>ALS</scp>)

Smethurst, Phillip; Sidle, Katie; Hardy, J. R.

doi:10.1111/nan.12206

Cited by 80 publications

(70 citation statements)

References 193 publications

(249 reference statements)

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“…The assumption that cortical neurons (Betz cells) are the first to become involved followed by the α-motor neurons, tends to favor Charcot's theory [35], namely, that ALS originates in the lateral funiculus (i. e., corticospinal tract, where the axons of the Betz cells are located) and only then affects the α-motor neurons in the anterior horn of the spinal cord [36]. The sources of the very first malfunctions within the protein TDP-43 in Betz cells are incompletely understood; but, it is conceivable that the further spread of the pathology to interconnected neurons takes place by means of the phylogenetically 'new' or recent monosynaptic contacts [9,29,32,[37][38][39][40][41]. Whether the same holds true not only for corticobulbar and corticospinal projections but also for corticorubral and corticostriatal connectivities is currently an open question.…”

Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Braak

Neumann

Ludolph

et al. 2017

Neurology International Open

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IntroductionAmyotrophic lateral sclerosis (ALS) is characterized by rapid progressive paralysis of the striated skeletal musculature [1,2]. The present review focuses on sporadic disease (sALS), which constitutes the majority of cases without a known genetic mutation. Clinically similar but inherited (familial) forms that display very diverse pathologies [3][4][5][6][7] are not taken into account here.The pathological process underlying sALS entails abnormal changes of an endogenous and predominantly intranuclear protein, TDP-43 (transactive response DNA-binding protein 43). Following nuclear clearance, the protein remains delocalized in the cytoplasm of susceptible nerve cells, where it undergoes defective phosphorylation and conformational change followed by ubiquitination, which ultimately prevent its re-entry into the nuclear compartment [7][8][9][10][11].The pathomechanisms that lead to the dysfunction and death of involved cells are still unknown. Along with a "loss of function" attributable to the loss of intranuclear TDP-43 expression accompanied by disrupted RNA metabolism, a "gain of function" mechanism owing to a noxious effect on cells by toxic TDP-43 forms has been discussed [7,12] Which Nerve Cell Types Develop TDP-43-immunoreactive Inclusions in sALS?The abnormal nuclear clearance and development of cytoplasmic TDP-43-immunopositive inclusions are confined to a few types ABsTr AC TThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions. E136Braak H et al. Does Sporadic Amyotrophic Lateral … Neurolo...

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Section: The Pathology In Cortical Betz Cells Differs From That In Bumentioning

confidence: 99%

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Braak

Neumann

Ludolph

et al. 2017

Neurology International Open

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“…Recent studies strongly suggest that, once formed, pernicious conformers of TDP-43 could spread through the nervous system in a prion-like fashion (Nonaka et al, 2013; Smethurst et al, 2015). This issue will likely prove crucial for a better understanding of TDP-43 proteinopathies.…”

Section: Introductionmentioning

confidence: 99%

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

Mompeán

Baralle

Buratti

et al. 2016

Front. Mol. Neurosci.

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TDP-43 is an essential RNA-binding protein forming aggregates in almost all cases of sporadic amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar dementia (FTLD) and other neurodegenerative diseases. TDP-43 consists of a folded N-terminal domain with a singular structure, two RRM RNA-binding domains, and a long disordered C-terminal region which plays roles in functional RNA regulatory assemblies as well as pernicious aggregation. Evidence from pathological mutations and seeding experiments strongly suggest that TDP-43 aggregates are pathologically relevant through toxic gain-of-harmful-function and/or harmful loss-of-native-function mechanisms. Recent, but not early, microscopy studies and the ability of TDP-43 aggregates to resist harsh treatment and to seed new pathological aggregates in vitro and in cells strongly suggest that TDP-43 aggregates have a self-templating, amyloid-like structure. Based on the importance of the Gln/Asn-rich 341–367 residue segment for efficient aggregation of endogenous TDP-43 when presented as a 12X-repeat and extensive spectroscopic and computational experiments, we recently proposed that this segment adopts a beta-hairpin structure that assembles in a parallel with a beta-turn configuration to form an amyloid-like structure. Here, we propose that this conformer is stabilized by an especially strong class of hypercooperative hydrogen bonding unique to Gln and Asn sidechains. The clinical existence of this conformer is supported by very recent LC-MS/MS characterization of TDP-43 from ex vivo aggregates, which show that residues 341–367 were protected in vivo from Ser phosphorylation, Gln/Asn deamidation and Met oxidation. Its distinct pattern of SDS-PAGE bands allows us to link this conformer to the exceptionally stable seed of the Type A TDP-43 proteinopathy.

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“…However, we prefer to use the term "prion-like" to differentiate sporadic AD and PD from rapidly progressive and infectious prion diseases, as PD and AD have not been shown to be rapidly progressive and contagious (Olanow and McNaught 2011;Iba 2013;Irwin et al 2013;Kaufman and Diamond 2013;Beekes et al 2014;Goedert et al 2014Goedert et al , 2015Brandel et al 2015;Walker and Jucker 2015;Walsh and Selkoe 2016). Available evidence from experimental studies performed in animal and in vitro models indicates that misfolded tau and a-synuclein proteins fulfill the criteria of prionlike proteins, that is to say, seeding/templating, propagation ("spreading"), and structurally differentiated conformations or conformers ("strains") (Aguzzi 2009;Clavaguera et al 2013b;Guo and Lee 2011;Bousset et al 2013;Watts et al 2013;Sanders et al 2014;Melki 2015;Peelaerts et al 2015;Smethurst et al 2015;Woerman et al 2015;Tuttle et al 2016; but see also Bernis et al 2015;Prusiner et al 2015;Supattapone 2015).…”

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confidence: 99%

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

109

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Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

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Review: Prion‐like mechanisms of transactive response DNA binding protein of 43 kDa (TDP‐43) in amyotrophic lateral sclerosis (ALS)

Cited by 80 publications

References 193 publications

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

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