Abstract
Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients’ fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention.
Highlights
Mitochondria are a vital organelle to support neuronal function and survival
We have previously found that in 12 healthy control fibroblast lines, CCCP treatment, which depolarizes the mitochondrial membrane potential ( m), for only 1 h triggers the recruitment of a small fraction of cytosolic LRRK2 and Parkin to mitochondria, prior to Miro1 and Mitofusin2 removal at 6 h detected by Western blotting (Figures 1A–C; Supplementary Figure 1A; Hsieh et al, 2016, 2019)
We examined whether LRRK2 and Parkin recruitment to damaged mitochondria was impaired in 7 fibroblast lines of frontal temporal lobar degeneration (FTLD) and parkinsonism patients or at-risk individuals with MAPT mutations, obtained from the Neurological Disorders and Stroke (NINDS) human and cell repository (Figure 1B; Supplementary Table 1)
Summary
Emerging evidence has revealed mitochondrial malfunction in a broad spectrum of neurological disorders (Misgeld and Schwarz, 2017). One such neurological condition is tauopathy, which is shared by multiple neurodegenerative diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontal temporal lobar degeneration (FTLD), and parkinsonism (Spillantini and Goedert, 2013; Medina, 2018). The main constituent of those filaments is tau protein, which is encoded by MAPT gene. Mutations in MAPT gene result in production of abnormal tau protein and promote tangle formation. Pathogenic MAPT mutations are detrimental to neuronal integrity and function (FusterMatanzo et al, 2018). Further characterization of mitophagy steps affected by pathogenic MAPT would help us understand better the underlying mechanisms and potential implications for disease pathogenesis
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