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

Abstract

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.

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

“…[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…”

“…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).…”

Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease

“…Our previous study detected tau overexpression (Gómez-Pinedo et al, 2016); we hypothesised that this finding may be linked to increased AICD expression resulting from APP pathway activation (Kim et al, 2003; Ghosal et al, 2009). Tau overexpression has also been reported by other researchers (Vintilescu et al, 2016), and the protein’s potential role in ALS has recently been reviewed (Moszczynski et al, 2018). Our study found no correlation with Notch, however.…”

Combined fused in sarcoma‐positive (FUS+) basophilic inclusion body disease and atypical tauopathy presenting with an amyotrophic lateral sclerosis/motor neurone disease (ALS/MND)‐plus phenotype

“…Tau pathology has also been described in association with ALS/MND, although tau deposition is not a feature of the typical inclusions of ALS/MND-TDP. Abnormal neuronal and glial tau phosphorylation has been suggested in the ALS/MND spectrum [5,6], but other studies have found that this is mostly low-Braak stage Alzheimer's type pathology and have not confirmed glial tau pathology [7]. A lack of predilection for enhanced tauopathy in FTLD-TDP, and of TDP-43 in FTLD-tau, suggests a lack of direct interaction [8].…”