Abstract
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.
Highlights
Our understanding of the pathobiology of amyotrophic lateral sclerosis (ALS) has evolved dramatically since its first description as a clinicopathological entity in 1874 by Charcot as a disorder of progressive muscular atrophy associated with spasticity [1]
We have shown that the phosphorylation of Thr175 of tau is associated with an enhanced exposure of the N-terminus of tau, increasing access to the tau phosphatase activating domain (PAD)
The conventional concept of ALS as a pure motor neuron disorder and a discrete disease has long been replaced by one of a multisystem disorder that is syndromic in nature and for which progressive neuropsychological deficits, including a frontotemporal spectrum disorder, are common
Summary
Our understanding of the pathobiology of amyotrophic lateral sclerosis (ALS) has evolved dramatically since its first description as a clinicopathological entity in 1874 by Charcot as a disorder of progressive muscular atrophy associated with spasticity [1]. This classical conceptualization of ALS has been significantly altered through two fundamental observations: firstly, that widespread frontotemporal dysfunction can occur in a significant proportion of patients [7,8,9,10,11]; and secondly, that a fundamental alteration in RNA metabolism, at multiple levels, is a core biological process for the majority of ALS cases [12] This latter postulate is supported by the observation of NCIs composed of a broad range of RNA binding proteins within degenerating motor neurons, but within cortical and subcortical neurons in ALS. Consistent with this concept, there is evidence that the RNA binding proteins Musashi 1 and 2 (MSI 1 and MSI 2, respectively), both highly expressed in mature neurons, form intranuclear complexes with oligomeric tau proteins in a concentration dependant manner [73] In doing so, these complexes significantly impair nucleocytoplasmic transport of NLS-containing cargo, a process that has been postulated to fundamental to the pathobiology of ALS and FTD [74]. We will examine the neuropathological, biochemical, and experimental evidence in support of pathological tau metabolism amongst a subset of ALS patients
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