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

Alan Mackay-Sim

doi:10.3390/brainsci11030403

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.

Highlights

Motor neuron diseases fall along a continuum of those affecting the lower motor neurons to those affecting the upper motor neurons
As an unbiased first step in understanding the cellular pathology of SPAST mutations, we investigated genome-wide gene expression in olfactory neural stem (ONS) cells from nine SPG4 patients with six different mutations in SPAST, comparing them with ONS cells from ten healthy controls [28]
We examined mitochondrial structure and function in patient-derived ONS cells from patients with compound heterozygous mutations in SPG7 and compared them with cells from patients with SPAST mutations and healthy controls [41]

Summary

Introduction

Motor neuron diseases fall along a continuum of those affecting the lower motor neurons (the motor neurons in the spinal cord controlling muscles) to those affecting the upper motor neurons Pure forms of HSP have signs and symptoms limited to the defining diagnosis of HSP, arising from degeneration of the corticospinal tract, whereas complicated forms have a variable set of other signs and symptoms that indicate widespread dysfunctions of many brain regions and many neuronal types: ataxia, seizures, intellectual disability, dementia, muscle atrophy, extrapyramidal disturbance, and peripheral neuropathy often specific to the genotype [4,5,6,7]. There were no abnormalities in grey or white matter in SPG3A patients including cerebral or cerebellar abnormalities [24] These numerous observations indicate systemic neurodegeneration that is not restricted to the cortical motor neurons projecting to the distal spinal cord: even patients with “pure” forms can have loss of white matter tracts more often seen in more “complicated’ forms. Indirect evidence for this can be gleaned from animal models and in cell lines in vitro using the molecular genetics approach of under- and over-expression of genes of interest

Pathological Phenotypes in HSP Patient-Derived Cells

Other Genotypes

Highly Connected Protein–Protein Interaction Networks of HSP Genes

15 Pure SPGs

Findings

Future Directions