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Review
. 2021 Mar 22;11(3):403.
doi: 10.3390/brainsci11030403.

Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery

Alan Mackay-Sim  1
Affiliations
Review

Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery

Alan Mackay-Sim. Brain Sci. .

Abstract

Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affecting the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across genotypes despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes.

Keywords: endoplasmic reticulum; motor neuron disease; neurodegeneration; protein-protein interaction network; spastic paraplegia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Predicted protein–protein interactions (PPI) networks for the six genes of the most common SPGs. (A) Direct interactions. (B) Second shell interactions.
Figure 2
Figure 2
Predicted PPI networks for direct interactions among 15 genes of pure SPGs.
Figure 3
Figure 3
Predicted PPI networks for second shell interactions among 15 genes of pure SPGs.
Figure 4
Figure 4
Predicted PPI networks direct interactions among 42 genes of complicated SPGs.
Figure 5
Figure 5
Predicted PPI networks for second shell interactions among 42 genes of complicated SPGs.
Figure 6
Figure 6
Predicted PPI networks for direct interactions among 57 genes of pure and complicated SPGs.
Figure 7
Figure 7
Predicted PPI networks for second shell interactions among 57 genes of pure and complicated SPGs.
See this image and copyright information in PMC

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