Dataset Information

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

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons. There is a pathological and genetic link between ALS and frontotemporal lobar degeneration (FTLD). Although FTLD is characterized by abnormal phosphorylated tau deposition, it is unknown whether tau is phosphorylated in ALS motor neurons. Therefore, this study assessed tau epitopes that are commonly phosphorylated in FTLD, including serine 396 (pS396), 214 (pS214), and 404 (pS404) in motor neurons from clinically pure sporadic ALS cases compared with controls. In ALS lower motor neurons, tau pS396 was observed in the nucleus or the nucleus and cytoplasm. In ALS upper motor neurons, tau pS396 was observed in the nucleus, cytoplasm, or both the nucleus and cytoplasm. Tau pS214 and pS404 was observed only in the cytoplasm of upper and lower motor neurons in ALS. The number of motor neurons (per mm2) positive for tau pS396 and pS214, but not pS404, was significantly increased in ALS. Furthermore, there was a significant loss of phosphorylated tau-negative motor neurons in ALS compared with controls. Together, our data identified a complex relationship between motor neurons positive for tau phosphorylated at specific residues and disease duration, suggesting that tau phosphorylation plays a role in ALS.

SUBMITTER: Stevens CH

PROVIDER: S-EPMC7967836 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Stevens Claire H CH Guthrie Natalie J NJ van Roijen Marloes M Halliday Glenda M GM Ooi Lezanne L

Journal of neuropathology and experimental neurology 20190701 7

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons. There is a pathological and genetic link between ALS and frontotemporal lobar degeneration (FTLD). Although FTLD is characterized by abnormal phosphorylated tau deposition, it is unknown whether tau is phosphorylated in ALS motor neurons. Therefore, this study assessed tau epitopes that are commonly phosphorylated in FTLD, including serine 396 (pS396), 214 (pS214), and 404 (pS404) in motor neur ...[more]

PMID: 31131395

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Project description:BACKGROUND:Amyotrophic lateral sclerosis (ALS) represents a devastating, progressive, heterogeneous, and the most common motor neuron (MN) disease. To date, no cure has been available for the condition. Studies with transgenic mice have yielded significant results that help us understand the underlying mechanisms of ALS. Nonetheless, none of more than 30 large clinical trials over the past 20 years proved successful, which led some researchers to challenge the validity of the preclinical models. METHODS:Human-induced pluripotent cells (iPSCs) were established by introducing Sendai virus into fibroblast cells. We established TDP-43 HES by inserting CAG-TDP43 (G298S) cassette or the CAG-EGFP cassette into PPP1R12C-locus of human embryonic stem cells (ESC, H9) by TALEN-mediated homologous recombination. iPSCs or HESC were differentiated to motor neurons and non-motor neuron as control. Relevant biomarkers were detected in different differentiated stages. TDP-43 aggregates, neurofilament, and mitochondria analyses were performed. RESULTS:In this study, using iPSCs-derived human MN from an ALS patient with a TDP43 G298S mutation and two sporadic ALS patients, we showed that both sporadic and familial ALS were characterized by TDP-43 aggregates in the surviving MN. Significantly higher neurofilament (NF) inclusion was also found in ALS MN compared with wild-type (WT) GM15 controls (P?<?0.05). The neurite mitochondria density was significantly lower in ALS MN than that in the control MNs. Transgenesis of TDP-43 G298S into AAVS locus in human embryonic stem cells reproduced phenotype of patient-derived G289S MN. By challenging MNs with a proteasome inhibitor, we found that MNs were more vulnerable to MG132, with some accompanying phenotype changes, such as TDP43 translocation, NF inclusion, mitochondria distribution impairment, and activation of caspase3. CONCLUSIONS:Our results suggested that changes in TDP43 protein, NF inclusion, and distribution impairment of mitochondria are common early pathology both in familial and sporadic ALS. These findings will help us gain insight into the pathogenesis of the condition and screen relevant drugs for the disease.

Dataset Information

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

Publications

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

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