Alterations in Tau Metabolism in ALS and ALS-FTSD

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.

Keywords: TDP-43; frontotemporal; motor neuron; phosphorylation; traumatic encephalopathy.