Research by Professor Andreas Prokop has identified a mechanism potentially explaining aspects of neurodegeneration, including inherited forms of Alzheimer's, Parkinson's, and motor neurone disease, which have been linked to genetic mutations.
The study, published in Current Biology, suggests that 'motor proteins' provide key answers. The Prokop group's research focuses on nerve fibers, known as axons, which transmit messages between the brain and body. Axons require constant material transport, performed by motor proteins moving along microtubules, to maintain long-term function.
Previous findings indicated that neurodegeneration could result from both mutations that disable motor protein cargo transport and those that cause motor protein hyperactivation (constant activity). A challenge has been explaining why these seemingly opposite mutations lead to similar forms of neurodegeneration.
Using fruit flies, which share genetic similarities with humans regarding nerve cell functions, the researchers observed that both disabling and hyperactivating mutations induced a similar axonal pathology: straight microtubule bundles deteriorated into areas of disorganized microtubule curling.
Further investigation revealed two distinct mechanisms that converge to cause this curling:
- Motor Protein Hyperactivation: Normal cargo transport along microtubules causes damage. Hyperactivation of motor proteins disrupts the balance between this damage and necessary repair mechanisms, leading to microtubule curling.
- Disabling Mutations: While causing less damaging traffic, disabling mutations deplete the supply of materials to axonal machinery, triggering oxidative stress. Oxidative stress negatively affects microtubule maintenance, resulting in the same type of microtubule curling seen with hyperactivation.
These findings suggest a 'dependency cycle of axon homeostasis,' where axon maintenance relies on a microtubule and motor protein-based transport system, which itself depends on this transport. Disruptions to this cycle, whether by oxidative stress or imbalances in microtubule damage/repair, can lead to axon decay. This model could explain why various gene mutations, linking to different cellular functions, can cause similar neurodegenerative diseases. The findings in fruit flies are expected to be applicable to humans due to fundamental genetic similarities.