Study Notes on Molecular Motors and Axonal Transport

Molecular Motors and Axonal Transport

Overview

  • Chapter 4 of Fundamental Neuroscience by Larry Squire et al.

Molecular Motors Definition

  • Molecular motors: Proteins that use ATP energy to generate movement along cellular structures, especially microtubules and microfilaments.

Types of Molecular Motors

Microtubule-Dependent Motor Proteins

Myosin II

  • Classification: Conventional myosin, characterized by two heads.

  • Heavy Chains: Motor domain, consisting of N-terminus (head domain) and C-terminus (tail).

  • Light Chains: Regulate motor function. Examples include synaptic transport proteins.

  • Mechanics: Myosin II uses ATP to facilitate movement along actin filaments.

  • Cross Bridge Cycle:

    • Involves thin actin and thick myosin filaments.

    • Regulation by proteins troponin and tropomyosin.

Microfilament-Dependent Motor Proteins

Kinesins

  • Kinesin-1 Structure:

    • Heterotetramer comprising two heavy chains (115–130 kDa) and two light chains (62–70 kDa).

    • Kinesins are involved in anterograde transport (toward the + end of microtubules).

    • Cargo Binding: Kinesin light chains bind to multiple types of organelles, including synaptic vesicle precursors and mitochondria.

    • Neuron-specific kinesin: kinesin 1A.

Dyneins

  • Structure: Comprised of large motor proteins with a motor domain and AAA rings.

  • Function: Serve as a retrograde motor for axonal transport, moving cargo toward the cell body.

  • Dynactin: A large complex crucial for dynein’s function, containing components that interact with microtubules and dynein itself.

Axonal Transport Mechanisms

Overview of Transport Types

  • Anterograde Transport: Mediated by kinesin towards the synapse.

  • Retrograde Transport: Mediated by dynein towards the cell body.

    • Involves processing and recycling of synaptic materials.

  • Mechanisms involve:

    • Fast Transport: Rates between 200-400 mm/day for anterograde and 50-100 mm/day for retrograde.

    • Slow Transport: Slower rates (0.3-3 mm/day for slow component 'a'; 2-8 mm/day for slow component 'b').

Fast Axonal Transport Rates

  1. Anterograde Transport:

    • Average: 200-400 mm/day (2-5 μm/s)

    • Moving structures include:

      • Golgi-derived vesicles

      • Mitochondria and synaptic vesicle proteins

  2. Retrograde Transport:

    • Average: 50-100 mm/day (0.5-1 μm/s)

    • Structures involved:

      • Endosomes and lysosomes.

Slow Axonal Transport

  • Slow Components: Move cytoskeletal and cytoplasmic constituents to the periphery through diffusion mechanisms.

    • Neurofilaments and cytoplasmic proteins travel at much slower rates reflecting their composition and function.

Differences in Dendrites

  • Dendritic microtubules may exhibit mixed polarity and different pathways for cytoplasmic deliveries.

  • Some mRNAs are selectively transported to dendrites, not axons, highlighting transport differences.

Interactions and Functional Dynamics

  • Neurofilaments move bidirectionally with kinesin-related proteins (plus-end) and dynein (minus-end) motors.

  • Axonal microtubules are oriented with plus ends distal to the cell body, aiding in directional transport.

Pathological Conditions Related to Transport Defects

Major Transport Defects

  • Dendritic and Axonal Functionality: Essential for synaptic transmission, neurotrophic factor signaling, and cellular maintenance.

Diseases Linked with Axonal Transport Defects:

  1. Amyotrophic Lateral Sclerosis (ALS):

    • Caused by mutations leading to neurofilament alteration and disruption in anterograde/retrograde transport.

  2. Charcot-Marie-Tooth Disease (CMT):

    • Inherited disorder causing sensory and motor neuron degeneration.

    • Associated with disrupted transport of synaptic vesicle proteins and mitochondrial function.

  3. Congenital Fibrosis of Extraocular Muscles (CFEOM):

    • Caused by mutations in kinesin-related genes affecting eye movement control.

Conclusion

  • The interplay between molecular motors, their structures, and axonal transport mechanisms is crucial for neuron functionality. Understanding these processes provides insight into the pathophysiology of several neurological diseases.