Tau Toxicity and Retrograde Axonal Transport
Abstract
One of the key characteristics of Alzheimer’s disease and other related disorders, known as tauopathies, is the accumulation of modified versions of the tau protein. These disease-related forms of tau are closely associated with the progressive degeneration of neurons observed in these diseases. The discovery that inherited mutations within the tau gene itself could lead to diseases like frontotemporal dementia provided some of the strongest evidence yet that modified versions of tau are likely to be an inducer of toxicity in disease. However, we still do not understand the mechanisms by which tau induces toxicity, which is a critical barrier toward understanding the disease and developing therapeutic interventions to slow the progression of neurodegeneration. One way to understand toxicity is to observe what processes are disrupted in disease and then determine if tau might play a role in that event. One of the earliest neurodegenerative events is the loss of synapses, the connections between neurons, followed by a dying back of the axon that projects away from the neuron. This is accompanied by a disruption to normal axonal transport. The longest axons in the human body can project up to a meter away from the cell body, which is the site of most protein production. In order to maintain a functional synapse at the end of the axon, the cell must transport material along microtubules in the anterograde (cell body to synapse) as well as retrograde (synapse to cell body) directions by using motor protein complexes, kinesin and cytoplasmic dynein, respectively. We, and other groups, found that disease-modified versions of tau can disrupt this process in several model systems. Many of these modifications only disrupted axonal transport in the anterograde direction in a process that depended on signaling pathways that changed the behavior of the kinesin motor protein. However, a subset of these modifications also disrupted transport in the retrograde direction, carried out by the dynein motor complex. We believe this indicates that tau is affecting dynein as part of its normal function and that the process is disrupted by the disease-related modifications we identified as affecting retrograde axonal transport. Here, we propose to identify the molecular mechanisms that underpin this event in order to better understand a novel mechanism of pathogenesis and provide potential targets for therapeutic intervention. We have two major aims in this proposal: (1) Identify the mechanism by which normal tau affects dynein function. (2) Identify how disease-related forms of tau affect dynein function in axonal transport. We will accomplish this by using mice with tau removed (Tau KO), mice expressing human tau (hTau), and normal mice to address these questions. We will examine the two major mechanisms by which tau could be regulating dynein activity. The first is by altering signaling pathways that are known to affect dynein-mediated axonal transport. We will identify how the presence of normal tau affects these pathways in the brain. The second possibility is that direct interaction between tau and dynein complex proteins alters its function in some way. We will identify any interactions between these proteins and determine how the interaction affects dynein function and localization in neurons. To address the second aim, we will use primary neurons isolated from the brains of the Tau KO mice. We will use lentiviruses to introduce modified versions of human tau that are known to disrupt retrograde axonal transport. Some of these will be toxic tau mutants that lead to early onset frontotemporal dementia and others will be changed to model phosphorylation changes that occur in AD. By introducing these toxic forms of tau and comparing them to the effects of normal tau, we can identify how the axonal transport process may be disrupted. We will examine how the modified versions of tau affect the regulatory signaling pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010174
Entities
People
- Benjamin Combs
Organizations
- Michigan State University
- United States Army