Increased Tau Phosphorylation in Motor Neurons From Clinically Pure Sporadic Amyotrophic Lateral Sclerosis Patients

Stevens, Claire H.; Guthrie, Natalie J; Roijen, Marloes van; Halliday, Glenda M.; Ooi, Lezanne

doi:10.1093/jnen/nlz041

Cited by 23 publications

(22 citation statements)

References 57 publications

(62 reference statements)

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“…[4][5] Specifically, cytoplasmic inclusions of hyperphosphorylated tau have been described in ALS post-mortem mCTX and spinal cord. [6][7][8] Here, our results expand on these findings and demonstrate a significant mis-localization of tau and pTau-S396 from the cytosol to synapses, reminiscent of AD. 32…”

Section: Discussionsupporting

confidence: 80%

“…3 Recent studies have begun to link alteration in tau phosphorylation to ALS pathogenesis in both sporadic and familial cases, 4,5 as cytoplasmic inclusions of hyperphosphorylated tau have been described in post-mortem motor cortex (mCTX) and spinal cord from ALS patients. [6][7][8] Tau is required for the trafficking of mitochondria across the axons to the synapses, 9 a crucial event to sustain the high energy requirement of neuronal cells. Hyperphosphorylation of key epitopes on tau impairs this process and disrupts mitochondrial localization, [10][11][12][13] thus contributing to axonal dysfunction and synapse loss in Alzheimer's disease (AD).…”

Section: Introductionmentioning

confidence: 99%

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Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Petrozziello

Bordt

Mills

et al. 2021

Preprint

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Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Petrozziello

Bordt

Mills

et al. 2021

Preprint

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“…The observation of pThr 175 tau pathology was subsequently confirmed in a separate cohort of motor neuron disease (MND) patients with concomitant FTD, including approximately 10% with non-descript neuronal aggregates and as with the earlier study, associated with pathological TDP-43 expression (114). Although not examined for the pThr 175 tau phospho epitope, ptau (pSer 396 , pSer 214 , and pSer 404 ) has been described in ALS cervical spinal cord and motor cortex in the cytosol and nuclei of motor neurons as diffuse immunoreactivity in the absence of fibril formation (115). The presence of nuclear tau in this latter series may be reflective of a neuronal stress response although no comment was made with respect to the presence or absence of nucleolar tau staining.…”

Section: Neuropathological and Biochemical Evidence Of Altered Tau Mementioning

confidence: 74%

Alterations in Tau Metabolism in ALS and ALS-FTSD

2020

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There is increasing acceptance that amyotrophic lateral sclerosis (ALS), classically considered a neurodegenerative disease affecting almost exclusively motor neurons, is syndromic with both clinical and biological heterogeneity. This is most evident in its association with a broad range of neuropsychological, behavioral, speech and language deficits [collectively termed ALS frontotemporal spectrum disorder (ALS-FTSD)]. Although the most consistent pathology of ALS and ALS-FTSD is a disturbance in TAR DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein (tau) metabolism can also be observed in ALS-FTSD, most prominently as pathological phosphorylation at Thr175 (pThr175tau). pThr175 has been shown to promote exposure of the phosphatase activating domain (PAD) in the tau N-terminus with the consequent activation of GSK3β mediated phosphorylation at Thr231 (pThr231tau) leading to pathological oligomer formation. This pathological cascade of tau phosphorylation has been observed in chronic traumatic encephalopathy with ALS (CTE-ALS) and in both in vivo and in vitro experimental paradigms, suggesting that it is of critical relevance to the pathobiology of ALS-FTSD. It is also evident that the co-existence of alterations in the metabolism of TDP-43 and tau acts synergistically in a rodent model to exacerbate the pathology of either.

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“…A related putative ALS cause is aggregation of misfolded SOD proteins [8]. Aberrations in chromosome 9 (C9orf72) with nucleotide repeats and hyperphosphorylated tau protein observed in sporadic ALS have also been proposed as potentially causative [9], as has mRNA dysmetabolism [7]. Markers of inflammation are elevated in ALS [10], and the hypothesis that inflammation plays a causative role in ALS is strengthened by observations of activated macrophages and the presence of dendritic cells in ALS spinal cord tissue [11].…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya

Röös

Wärmländer

Meyer

et al. 2020

Biol Trace Elem Res

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.

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Increased Tau Phosphorylation in Motor Neurons From Clinically Pure Sporadic Amyotrophic Lateral Sclerosis Patients

Cited by 23 publications

References 57 publications

Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

Alterations in Tau Metabolism in ALS and ALS-FTSD

Amyotrophic Lateral Sclerosis After Exposure to Manganese from Traditional Medicine Procedures in Kenya

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