The Neurotoxic Tau45-230 Fragment Accumulates in Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis Subjects

Vintilescu, Claudia Roxana; Afreen, Sana; Rubino, Ashlee E; Ferreira, Adriana

doi:10.2119/molmed.2016.00095

Cited by 18 publications

(18 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The presence of tau pathology has also been described in both sporadic and familial ALS case reports (Orrell et al, 1995 ; Soma et al, 2012 ; Dobson-Stone et al, 2013 ; Nakamura et al, 2014 ; Takeuchi et al, 2016 ). Additionally, several more recent studies have reported an elevation in phosphorylated and truncated tau protein in both hippocampal and spinal cord neurons of various ALS populations (Gómez-Pinedo et al, 2016 ; Vintilescu et al, 2016 ).…”

Section: Als-ftsd: Neuropathological Characterizationmentioning

confidence: 98%

Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis—Frontotemporal Spectrum Disorder (ALS-FTSD). A Review

2018

View full text Add to dashboard Cite

Approximately 50–60% of all patients with amyotrophic lateral sclerosis (ALS) will develop a deficit of frontotemporal function, ranging from frontotemporal dementia (FTD) to one or more deficits of neuropsychological, speech or language function which are collectively known as the frontotemporal spectrum disorders of ALS (ALS-FTSD). While the neuropathology underlying these disorders is most consistent with a widespread alteration in the metabolism of transactive response DNA-binding protein 43 (TDP-43), in both ALS with cognitive impairment (ALSci) and ALS with FTD (ALS-FTD; also known as MND-FTD) there is evidence for alterations in the metabolism of the microtubule associated protein tau. This alteration in tau metabolism is characterized by pathological phosphorylation at residue Thr175 (pThr175 tau) which in vitro is associated with activation of GSK3β (pTyr216GSK3β), phosphorylation of Thr231tau, and the formation of cytoplasmic inclusions with increased rates of cell death. This putative pathway of pThr175 induction of pThr231 and the formation of pathogenic tau inclusions has been recently shown to span a broad range of tauopathies, including chronic traumatic encephalopathy (CTE) and CTE in association with ALS (CTE-ALS). This pathway can be experimentally triggered through a moderate traumatic brain injury, suggesting that it is a primary neuropathological event and not secondary to a more widespread neuronal dysfunction. In this review, we discuss the neuropathological underpinnings of the postulate that ALS is associated with a tauopathy which manifests as a FTSD, and examine possible mechanisms by which phosphorylation at Thr175tau is induced. We hypothesize that this might lead to an unfolding of the hairpin structure of tau, activation of GSK3β and pathological tau fibril formation through the induction of cis-Thr231 tau conformers. A potential role of TDP-43 acting synergistically with pathological tau metabolism is proposed.

show abstract

Section: Als-ftsd: Neuropathological Characterizationmentioning

confidence: 98%

Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis—Frontotemporal Spectrum Disorder (ALS-FTSD). A Review

2018

View full text Add to dashboard Cite

show abstract

“…). Further investigations will be needed to clarify whether ectopic tau accumulation and its colocalization are intensified in TDP‐43‐susceptible areas, such as the medial temporal tip or spinal motor neurons, in patients with ALS/FTLD‐TDP . The results of such studies will provide further evidence that ALS/FTLD‐TDP pathogenesis could be associated with the facilitation of abnormal tau and the accumulation of other proteins.…”

Section: Resultsmentioning

confidence: 99%

“…Although this pathologically wide spread of tau accumulation in patients with ALS did not correlate with the severity of TDP‐43 pathology, neurons harboring tau inclusions were notably demonstrating a loss of intranuclear staining for native TDP‐43 . Vintilescu et al demonstrated an abnormal accumulation of tau 45–230 fragments in the spinal cord and the primary motor cortex of patients with ALS . In a recent investigation using an animal model, tau accumulation was increased in tau transgenic mice (P301L) with a GRN mutation in comparison with those without the mutation .…”

Section: Tau and Other Protein Pathologies In Als/ftld‐tdpmentioning

confidence: 98%

“…73 Vintilescu et al demonstrated an abnormal accumulation of tau fragments in the spinal cord and the primary motor cortex of patients with ALS. 74,75 In a recent investigation using an animal model, tau accumulation was increased in tau transgenic mice (P301L) with a GRN mutation in comparison with those without the mutation. 76 This suggests that progranulin reduction caused by GRN mutations may be causative for tau accumulation.…”

Section: Tau and Other Protein Pathologies In Als/ftld-tdpmentioning

confidence: 99%

See 1 more Smart Citation

Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

Takeda

2017

Neuropathology

View full text Add to dashboard Cite

Transactivation response DNA-binding protein 43 kDa (TDP-43) has been regarded as a major component of ubiquitin-positive/tau-negative inclusions of motor neurons and the frontotemporal cortices in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles (NFT), an example of tau-positive inclusions, are biochemically and morphologically distinguished from TDP-43-positive inclusions, and are one of the pathological core features of Alzheimer disease (AD). Although ALS/FTLD and AD are distinct clinical entities, they can coexist in an individual patient. Whether concurrence of ALS/FTLD-TDP-43 and AD-tau is incidental is still controversial, because aging is a common risk factor for ALS/FTLD and AD development. Indeed, it remains unclear whether the pathogenesis of ALS/FTLD is a direct causal link to tau accumulation. Recent studies suggested that AD pathogenesis could cause the accumulation of TDP-43, while abnormal TDP-43 accumulation could also lead to abnormal tau expression. Overlapping presence of TDP-43 and tau, when observed in a brain during autopsy, should attract attention, and should initiate the search for the pathological substrate for this abnormal protein accumulation. In addition to tau, other proteins including α-synuclein and amyloid β should be also taken into account as candidates for an interaction with TDP-43. Awareness of a possible comorbidity between TDP-43, tau and other proteins in patients with ALS/FTLD will be useful for our understanding of the influence of these proteins on the disease development and its clinical manifestation.

show abstract

“…Moreover, in CSF derived from TBI patients, a 30-50 kDa tau fragment was found to correlate with the extent of axonal damage [143]. Lastly, in CSF derived from either lumbar or cervical puncture from amyotrophic lateral sclerosis (ALS) patients the neurotoxic 17 kDa fragment produced by calpain cleavage was found to be elevated compared to controls [144].…”

Section: Tau Truncated Formsmentioning

confidence: 95%

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Llorens¹,

Villar‐Piqué²,

Candelise³

et al. 2019

Cognitive Disorders

View full text Add to dashboard Cite

Tau is a microtubule-associated protein, whose main function is the modulation of the stability of axonal microtubules. In physiological conditions tau is abundant in neurons while its expression in glial populations is low and restricted to astrocytes and oligodendrocytes. The aggregation of tau in neurofibrillary or gliofibrillary tangles is the main hallmark of tauopathies, a complex group of human neurodegenerative conditions where tau hyper-phosphorylation causes its increased insolubility and aggregation leading to tangle formation and microtubule destabilization. Tau can be detected in biological fluids in physiological and pathological conditions. In several neurodegenerative dementias, either associated or not to a primary tauopathy, tau levels are altered in a diseasespecific pattern, which can be used as a biomarker for disease diagnosis and prognosis. The study of tau levels in biological fluids has been mainly performed in the cerebrospinal fluid (CSF), although the recent development of ultrasensitive techniques allows the robust quantification of tau in blood-based biofluids such as serum and plasma. The presence of elevated total-tau in the CSF is assumed to reflect the degree of axonal damage in the brain tissue. Consequently, highest total-tau CSF levels are found in sporadic Creutzfeldt-Jakob disease, which is characterized by massive neuronal damage and a rapid progressive course. Elevated total-tau is also detected in Alzheimer's disease and dementia with Lewy bodies, while in other dementia conditions such as vascular dementia, frontotemporal dementia and corticobasal degeneration are unchanged, inconclusive or not determined. Additionally, total-tau rises temporarily due to cerebral infarction. In contrast, elevated phospho-tau levels seem to be restricted to Alzheimer's disease pathology, most likely mirroring the presence of the hyper-phosphorylated form in the brain tissue, although phospho-tau levels are mainly unaffected in tauopathies. Additionally, isoforms and different structural and truncated tau forms have also been reported to be altered in neurodegenerative dementias. In this complex scenario the diagnostic accuracy of diverse tau forms as disease-specific biomarkers needs to be established. In this chapter, we summarize the current knowledge on the alterations of diverse tau forms

show abstract

The Neurotoxic Tau45-230 Fragment Accumulates in Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis Subjects

Cited by 18 publications

References 70 publications

Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis—Frontotemporal Spectrum Disorder (ALS-FTSD). A Review

Phosphorylation of Threonine 175 Tau in the Induction of Tau Pathology in Amyotrophic Lateral Sclerosis—Frontotemporal Spectrum Disorder (ALS-FTSD). A Review

Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Contact Info

Product

Resources

About