Tau Accumulation in Degradative Organelles is Associated to Lysosomal Stress

Abstract

Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction

“…Video S1). Nonetheless, these findings support previous notions of tau interfacing with the autophagic/lysosomal system 84–92 , highlighting that a minor fraction of hyperphosphorylated tau could directly affect lysosomal function.…”

“…Mapt), which has been previously shown to be disrupted in apoE4-expressing neuronal cells. 12,21,82,83 While we did not consistently detect tau in lysosomes by mass spectrometry, it has recently been reported to spread through lysosomes 84,85 , and could be speculated to also influence lysosomal function. As expected, we found S202/T205-phosphorylated tau to be present within lysosomes of iPSC-derived human neurons, albeit at very low levels (Suppl.…”

“…While silencing App or its associated γ-secretase Psen2 had no effect on lysosomal function in apoE4-expressing cells, tau removal significantly improved lysosomal function. These findings highlight a discordance between how the two classical AD aggregates affect cellular function, and reveal a vicious cycle between tau and lysosomes: While lysosomal dysfunction on one hand results in tau accumulation 84,86,88,89,91 , we find that tau accumulation itself impairs lysosomal activity. This vicious cycle becomes particularly intriguing in the context of apoE4-associated lysosomal impairment.…”