Abstract
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.
Highlights
Immunohistochemistry study of three SPAST Hereditary spastic paraplegia (HSP) cases showed altered mitochondrial distribution in the cell body of spinal cord lower and upper motor neurons, with mitochondria being restricted to the periphery of the neuronal soma, in contrast to uniformly distributed mitochondria in control cells [31]
Similar results were observed in neurons that were generated from patient-derived Induced pluripotent stem (iPS) cells: epothilone D and noscapine rescued peroxisome axon transport deficits and ameliorated axonal degeneration induced by hydrogen peroxide [80]
It is expensive in time and money to generate iPS cells and this may be limiting for research on rare diseases like HSP
Summary
Cerebral white matter alterations in HSP patients were quantified using diffusion tensor imaging (DTI), a widely used magnetic resonance imaging technique. Brain Sci. 2018, 8, 142 tract are consistent with the motor symptoms of the disease, white matter disturbances are not confined to the corticospinal tract and corpus callosum with involvement at the whole brain level, frontal and temporal lobes, cerebellum, and other regions These observations were made with a variety of DTI techniques, fractional anisotropy being the commonly quantified measure. It is worth noting that the extent of affected regions may be underestimated due to the limits of DTI sensitivity [26] These changes are consistent with widely distributed axonal damage in the white matter of the brain, including the corticospinal tract, which contains the axons of the motor neurons projecting to the lower motor neurons in the distal spinal cord, whose degeneration is responsible for the clinical manifestations of HSP. A major aim for researchers is to understand the cellular mechanisms leading to degeneration of the corticospinal tract
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