Localization of Axonal Motor Molecules Machinery in Neurodegenerative Disorders

Fulvio Florenzano

doi:10.3390/ijms13045195

Abstract

Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of the cell body. All these actions are executed through cytoskeleton, transport and regulatory elements that appear to be disrupted in neurodegenerative diseases. Motor-driven transport both supplies and clears distal cellular portions with proteins and organelles. This transport is especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings. Thus, any disturbance of axonal transport may have severe consequences for neuronal function and survival. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylation, but also in their subcellular distribution within populations of neurons, which are selectively affected in the course of neurodegenerative diseases. The implications of this altered subcellular localization and how this affects axon survival and neuronal death still remain poorly understood, although several hypotheses have been suggested. Furthermore, cytoskeleton and transport element localization can be selectively disrupted in some disorders suggesting that specific loss of the axonal functionality could be a primary hallmark of the disorder. This can lead to axon degeneration and neuronal death either directly, through the functional absence of essential axonal proteins, or indirectly, through failures in communication among different cellular domains. This review compares the localization of cytoskeleton and transport elements in some neurodegenerative disorders to ask what aspects may be essential for axon survival and neuronal death.

Highlights

Axon degeneration is perhaps the most common and dangerous damage after brain injury for several reasons
Damage spreading may represent the pathogenic convergence of different types of insults in the same anatomical area on a common neurodegenerative disease mechanism
―dendritopathy‖ has still not been characterized; and it is generally believed that damage to a dendritic domain can remain localized without spreading to the other dendritic branches or without generating a retrograde death reaction. The reasons for this resistance can be found in the different dendrite spatial arrangement, but it is highly conceivable that differences in protein transport mechanisms make the dendrites less susceptible to retrograde death phenomena compared to axons

Summary

Introduction

Axon degeneration is perhaps the most common and dangerous damage after brain injury for several reasons. The majority of brain insults are initially restricted only to a brain region. The axons passing through or terminating on the damaged region begin to degenerate, propagating the damage to other brain regions. This subsequent damage spreading is often observed to produce clinical complications, which may represent the disease degenerative course and gradually worsen the patient’s quality of life. Damage spreading may represent the pathogenic convergence of different types of insults in the same anatomical area on a common neurodegenerative disease mechanism. Damage spreading is a mechanism playing a variable role in probably all neurodegenerative conditions

Axon: The Most Sensitive Neuronal Domain

Transport Machinery

Cytoskeleton Composition of Axons Is Related to Environmental Stimuli

Findings

Conclusions