Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS.

Oge Gozutok,P Hande Ozdinler,Benjamin Ryan Helmold

doi:10.3390/brainsci11050578

Abstract

Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions.

Highlights

Upper motor neurons (UMNs) are an important component of the motor neuron circuitry [1,2,3,4,5,6]
Mutations in these genes have been well-reported and documented in hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) patients, and some animal models have already been generated to bring a mechanistic insight for the underlying causes of UMN degeneration [17,18,19,20,21]
In an effort to understand the dynamics of protein-protein interaction domains and how they are perturbed with respect to UMN diseases, we investigated the binding partners of proteins that are coded by the genes that are reported to be mutated in HSP and PLS

Summary

Introduction

Upper motor neurons (UMNs) are an important component of the motor neuron circuitry [1,2,3,4,5,6]. Since movement starts in the brain, the UMNs have the unique ability to convey the cerebral cortex’s input to spinal cord targets such that voluntary movement can be initiated and modulated [1,13]. Their degeneration severs the contact between the brain and spinal cord and leads to paralysis in patients. UMNs are one of the largest neurons in the brain and one of the most polarized: apical dendrites extend to the top layers of the brain and the axons project to the sacral regions of the spinal cord For this amazingly elaborate neuron to be healthy and functional, numerous cellular events and canonical pathways must be active

Methods

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Discussion

Conclusion