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

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.

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Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽

10.3390/cells10071678 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1678

Author(s):

Liriopé Toupenet Marchesi ◽

Marion Leblanc ◽

Giovanni Stevanin

Keyword(s):

Nervous System ◽

Motor Neurons ◽

Neurological Disorders ◽

Hereditary Spastic Paraplegia ◽

Current Knowledge ◽

Spastic Paraplegia ◽

Functional Convergence ◽

The Common ◽

Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

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Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery

Brain Sciences ◽

10.3390/brainsci8080142 ◽

2018 ◽

Vol 8 (8) ◽

pp. 142 ◽

Cited By ~ 4

Author(s):

Gautam Wali ◽

Carolyn Sue ◽

Alan Mackay-Sim

Keyword(s):

Motor Neurons ◽

Cellular Level ◽

Lower Limbs ◽

Cell Models ◽

Spastic Paraplegia ◽

Disease Mechanism ◽

Know How ◽

First Case ◽

Hsp Genes ◽

Stem Cell Models

Hereditary spastic paraplegia is an inherited, progressive paralysis of the lower limbs first described by Adolph Strümpell in 1883 with a further detailed description of the disease by Maurice Lorrain in 1888. Today, more than 100 years after the first case of HSP was described, we still do not know how mutations in HSP genes lead to degeneration of the corticospinal motor neurons. This review describes how patient-derived stem cells contribute to understanding the disease mechanism at the cellular level and use this for discovery of potential new therapeutics, focusing on SPAST mutations, the most common cause of HSP.

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GCH1 mutations in hereditary spastic paraplegia

10.1101/2021.01.14.21249305 ◽

2021 ◽

Author(s):

Parizad Varghaei ◽

Grace Yoon ◽

Mehrdad A Estiar ◽

Simon Veyron ◽

Nicolas Dupre ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Monozygotic Twins ◽

Enrichment Analysis ◽

Lower Limbs ◽

Pathway Enrichment Analysis ◽

Disruptive Effect ◽

Spastic Paraplegia ◽

Phenotypic Differences ◽

Whole Exome ◽

Hsp Genes

AbstractGCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson’s disease (PD) and tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have also been reported in five patients with hereditary spastic paraplegia (HSP). In this study, a total of 400 HSP patients (291 families) from different centers across Canada were analyzed by whole exome sequencing (WES). Three patients with GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. Both variants were predicted to be likely pathogenic. The three patients presented with childhood-onset spasticity in the lower limbs, hyperreflexia and abnormal plantar responses. Only one of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, and they responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares similar processes and pathways with other HSP-associated genes, and structural analysis of the variants suggested a disruptive effect. In conclusion, GCH1 mutations may also cause HSP; therefore, we suggest including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors could play a role in the clinical presentation of the disease.

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Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia

Scientific Reports ◽

10.1038/s41598-021-95995-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gautam Wali ◽

Shlomo Berkovsky ◽

Daniel R. Whiten ◽

Alan Mackay-Sim ◽

Carolyn M. Sue

Keyword(s):

Neurodegenerative Diseases ◽

Cell Morphology ◽

Hereditary Spastic Paraplegia ◽

High Throughput Screening ◽

Cellular Level ◽

Dependent Manner ◽

Spastic Paraplegia ◽

Causative Gene ◽

Compound Libraries ◽

The Many

AbstractA central need for neurodegenerative diseases is to find curative drugs for the many clinical subtypes, the causative gene for most cases being unknown. This requires the classification of disease cases at the genetic and cellular level, an understanding of disease aetiology in the subtypes and the development of phenotypic assays for high throughput screening of large compound libraries. Herein we describe a method that facilitates these requirements based on cell morphology that is being increasingly used as a readout defining cell state. In patient-derived fibroblasts we quantified 124 morphological features in 100,000 cells from 15 people with two genotypes (SPAST and SPG7) of Hereditary Spastic Paraplegia (HSP) and matched controls. Using machine learning analysis, we distinguished between each genotype and separated them from controls. Cell morphologies changed with treatment with noscapine, a tubulin-binding drug, in a genotype-dependent manner, revealing a novel effect on one of the genotypes (SPG7). These findings demonstrate a method for morphological profiling in fibroblasts, an accessible non-neural cell, to classify and distinguish between clinical subtypes of neurodegenerative diseases, for drug discovery, and potentially for biomarkers of disease severity and progression.

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