Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism

Combs, Benjamin; Christensen, Kyle R; Richards, Collin; Kneynsberg, Andrew; Mueller, Rebecca L; Morris, Sarah; Morfini, Gerardo; Brady, Scott T.; Kanaan, Nicholas M.

doi:10.1523/jneurosci.1914-20.2021

Cited by 10 publications

(6 citation statements)

References 76 publications

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“…It is very likely that the 14 days of in vitro life of our cultured neurons are not enough for NFTs formation, but sufficient to observe heavy deficits in axonal trafficking. Our data are in agreement with the recent literature in other AD models reporting a decrease in the vesicular speeds in THY-Tau22 axons [57].…”

Section: Discussionsupporting

confidence: 93%

Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release

et al. 2023

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The discovery of the neuronal expression of the serine protease tissue-type plasminogen activator (tPA) has opened new avenues of research, with important implications in the physiopathology of the central nervous system. For example, the interaction of tPA with synaptic receptors (NMDAR, LRP1, Annexin II, and EGFR) and its role in the maturation of BDNF have been reported to influence synaptic plasticity and neuronal survival. However, the mechanisms regulating the neuronal trafficking of tPA are unknown. Here, using high-resolution live cell imaging and a panel of innovative genetic approaches, we first unmasked the dynamic characteristics of the dendritic and axonal trafficking of tPA-containing vesicles under different paradigms of neuronal activation or inhibition. We then report a constitutive exocytosis of tPA- and VAMP2-positive vesicles, dramatically increased in conditions of neuronal activation, with a pattern which was mainly dendritic and thus post-synaptic. We also observed that the synaptic release of tPA led to an increase of the exocytosis of VGlut1 positive vesicles containing glutamate. Finally, we described alterations of the trafficking and exocytosis of neuronal tPA in cultured cortical neurons prepared from tau-22 transgenic mice (a preclinical model of Alzheimer’s disease (AD)). Altogether, these data provide new insights about the neuronal trafficking of tPA, contributing to a better knowledge of the tPA-dependent brain functions and dysfunctions.

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Section: Discussionsupporting

confidence: 93%

Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release

et al. 2023

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“…In contrast, in tau P301L knock-in mice in which the mutated protein is transcribed and expressed at physiological levels, there are reduced levels of tau phosphorylation and mitochondrial anterograde axonal transport defects are less severe compared to those of transgenic mouse models overexpressing the human P301L mutation ( Gilley et al, 2012 ). A recent study revealed a R5L mutation in the tau protein inhibits axonal transport by activating protein phosphatase 1 (PP1) ( Combs et al, 2021 ). In hippocampal neurons of rats, R5L tau selectively interacts with PP1α and PP1γ, significantly increasing PP1 activity.…”

Section: Axonal Transport Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Yang

Lian

et al. 2023

Front. Mol. Neurosci.

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Many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.

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“…For example, intronic mutations (and some missense mutations) alter the regulation of tau splicing and the resulting composition of tau isoforms expressed [30][31][32] . Individual missense mutations have been shown to differ from wild-type (WT) in one or more properties including aggregation propensity [33][34][35] , cellular aggregate seeding 36,37 , microtubule binding and dynamics 35,[38][39][40][41] , protein interaction partners 42,43 , post-translational modifications 44,45 , engagement and processing by the protein quality control machinery 43,[46][47][48] and axonal functions 49,50 . Mice expressing individual tau missense mutants produce distinct phenotypic profiles in regards to cellular dysfunction, patterns and timing of tau aggregate pathology, and behavioral deficits 51 .…”

Section: Introductionmentioning

confidence: 99%

Disease associated mutations in tau encode for changes in aggregate structure conformation

Sun

Patel

Kang

et al. 2023

Preprint

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The accumulation of tau aggregates is associated with neurodegenerative diseases collectively known as tauopathies. Tau aggregates (fibrils) isolated from different tauopathies such as Alzheimer's Disease, corticobasal degeneration and progressive supranuclear palsy have distinct Cryo-EM structures with respect to their packed fibril cores. To understand the mechanisms by which tau can be sensitized to form distinct aggregate conformations, we created a panel of tau variants encoding for individual disease-associated missense mutations in full-length 0N4R tau (WT and 36 mutants). We developed a high-throughput protein purification platform for direct comparison of tau variants in biochemical assays. Structural analysis of the protease-resistant core of tau aggregates formed in vitro reveals that mutations can promote aggregate core packing distinct from that produced by WT tau. Comparing aggregate structure changes with aggregation kinetic parameters for tau mutants revealed no clear linkage between these two aggregation properties. We also found that tau mutation-dependent alterations of tau aggregate structure are not readily explained by current tau fibril structure data. This is the first study to show the broad potential of tau mutations to alter the packed core structures contained within aggregated tau and sheds new insights into the molecular mechanisms underlying the formation of tau aggregate structures that may drive their associated pathology in disease.

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Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism

Cited by 10 publications

References 76 publications

Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release

Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

Disease associated mutations in tau encode for changes in aggregate structure conformation

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