The cause of hereditary spastic paraplegia

The movement of an animal depends on the ability of neurons to carry signals from the center of the cell (cell body) to narrow projections known as axons. In humans, axons can reach up to a meter in length. This implies that they can be approximately one hundred thousand times longer than the cell body, which would be equivalent to a person of average height being able to physically contact someone located at a distance of between 100 and 200 kilometers.

The achievement of maintaining the structure and function of such long axons requires different communication pathways, whose defects are related to the development of hereditary spastic paraplegia. In this disease, the axons of the longest neurons (motor and sensory) undergo progressive degeneration, typically from the farthest ends of the cell body. The endoplasmic reticulum is a cellular structure that shows physical continuity and extends throughout all regions of the neuron, for which reason it has been called “a neuron within a neuron”, and genetic mutations that affect its organization are a of the main causes of hereditary spastic paraplegia. This disease is characterized by symptoms such as spasticity, paralysis and/or lack of sensation in the legs. However, very little is known about the function of the axonal endoplasmic reticulum and its contribution to neurodegeneration processes.

One of the genes related to the endoplasmic reticulum and hereditary spastic paraplegia is RTN2.

A recent study, carried out by a team that includes Rebecca C. Smith, from the University of Cambridge in the United Kingdom, and Juan José Pérez Moreno, from the Institute of Biomedicine of Seville (IBiS) and the University of Seville (US) , in Spain both institutions, explores for the first time the specific role of the RTN2 gene in the organization of the endoplasmic reticulum of the most distal part of the axon, the presynaptic region, through which the neuron communicates with other cells (another neuron or a muscle cell). In this region, the endoplasmic reticulum forms an interconnected network of tubules and cisterns.

Using the model organism Drosophila (fruit fly), it has been observed that the loss of function of the RTN2 equivalent gene leads to a specific reduction of tubules at the presynaptic level. These defects do not affect the ability of the endoplasmic reticulum to store calcium, but rather the ability to introduce it into the neuron from outside the cell, which is essential for synaptic function, which is reduced in animals with lack of function. from RTN2.

Artistic recreation of neurons in the process of degeneration. (Illustration: Amazings/NCYT)

One of the pathways for calcium uptake is mediated by the endoplasmic reticulum, through contacts with the cell membrane. In the new study, it has been seen that the levels of a specific protein that accumulates on the surface of the endoplasmic reticulum, STIM, correlate with the observed defects, concluding that the loss of endoplasmic reticulum surface in RTN2 mutants leads to less mediated contacts. by STIM between the endoplasmic reticulum and the plasma membrane, and therefore to a lower calcium uptake during neuronal activity. The results obtained indicate a new mechanism by which the organization of the endoplasmic reticulum controls synaptic function, and suggest a possible pathway by which it could cause hereditary spastic paraplegia.

The study is titled “Drosophila SPG12 ortholog, reticulon-like 1, governs presynaptic ER organization and Ca²⁺ dynamics”. And it has been published in the Journal of Cell Biology. (Source: US)