Mis-Localization of LSD1 Underlies Tau-Mediated Neurodegeneration

Post by Shireen Parimoo

What's the science?

One of the hallmarks of Alzheimer’s disease is the presence of neurofibrillary tangles made up of misfolded tau proteins. The neurofibrillary tangles initially accumulate in regions of the medial temporal lobe, such as the hippocampus, before spreading to the rest of the brain, resulting in neuronal death. LSD1 is an enzyme that is typically found in the nucleus of cells and is important for neuronal survival. In the presence of tau pathology, however, LSD1 is mislocalized to the cell cytoplasm along with the neurofibrillary tangles. The Deletion of LSD1 from neurons also leads to neurodegeneration, suggesting that it might contribute to tau-related disorders like Alzheimer’s disease. This week in PNAS, Engstrom and colleagues used histological and RNA sequencing techniques to investigate the mechanistic role of LSD1 in tau-mediated neurodegeneration.

How did they do it?

The authors used wild-type and PS19-Tau transgenic mice that exhibited tau pathology in the brain, beginning in the temporal lobes at approximately 8 months old (Tau mice). First, they used immunofluorescence to compare the localization of LSD1 in hippocampal and cortical neurons of the Tau and wild-type mice. They then bred mice with an Lsd1 gene deletion (control mice) with the Tau mice (Tau-Lsd1 mice) to explore the interaction between tau and LSD1. Heterozygous deletion of the Lsd1 gene reduces the expression of the LSD1 enzyme. In addition to recording motor function and survival of the Tau-Lsd1 mice, the authors used immunohistochemistry to assess neurodegeneration and the localization of LSD1 in hippocampal cells. Next, they identified the molecular pathways that are altered in the presence of tau pathology using RNA sequencing, which allowed them to compare the gene expression profiles of the Lsd1, Tau, and Tau-Lsd1 mice. Finally, they injected LSD1 into hippocampal neurons of 8-month-old Tau mice and assessed the effects of LSD1 overexpression three months later.

What did they find?

LSD1 was localized to the nucleus of hippocampal and cortical neurons in wild-type mice. In contrast, LSD1 was found in both the nucleus and cytoplasm of Tau mice, and this shift to the cytoplasm was exacerbated in the Tau-Lsd1 mice. Both the Tau and Tau-Lsd1 mice exhibited signs of motor dysfunction around 6 months old after tau pathology was evident, but in contrast to the Tau mice, the Tau-Lsd1 mice were severely paralyzed by 12 months old. Similarly, Tau-Lsd1 mice had greater hippocampal neurodegeneration at 10 months old and lower rates of survival as compared to the Tau mice. Thus, the reduced expression and mislocalization of LSD1 occurs in the presence of pathological tau and accelerates the onset of death.

The gene expression profiles of Tau-Lsd1 mice were markedly different compared to control mice. Tau-induced gene expression changes were more severe when LSD1 was reduced. Overexpressing LSD1 in the hippocampus of Tau mice further led to gene expression changes in the opposite direction to the Tau-Lsd1 mice, as well as lower cell death. However, LSD1 overexpression did not rescue motor function and the mice still developed paralysis. Overall, these findings suggest that the interaction between Tau and LSD1 results in neurodegeneration and paralysis by altering the expression of cellular proteins, which can be partially rescued by overexpressing LSD1.

What's the impact?

This is the first study to demonstrate the mechanism by which tau accumulation in neurons interacts with the LSD1 enzyme, providing deeper insight into how neurodegeneration occurs in tauopathies. The finding that some of the adverse effects of pathological tau can be mitigated by overexpressing LSD1 is particularly exciting. This discovery paves the way for future research to further explore whether motor function can also be rescued by altering LSD1 expression in other regions of the brain and raises the possibility that tauopathies such as Alzheimer’s disease can be targeted therapeutically through the LSD1 pathway.

Engstrom et al. The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration. PNAS (2020).Access the original scientific publication here.