| Abstract |
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of
inherited motor neuron diseases characterized by progressive spasticity
and weakness of the lower limbs. Mutations in the Spastic Paraplegia
Gene 11 (SPG11), encoding spatacsin, cause the most frequent form of
autosomal recessive HSP. SPG11 patients are clinically distinguishable
from most other HSPs, by severe cortical atrophy and presence of a thin
corpus callosum (TCC), associated with cognitive deficits.
Partly due to lack of a relevant disease model, the distinct cellular and
molecular mechanisms modulating these symptoms have not been deciphered
so far. We generated induced pluripotent stem cells (iPSCs) from three
SPG11 patients, having heterozygous nonsense and/or splice site
mutations, and two age matched controls. We differentiated these iPSCs
into forebrain neuronal cells and investigated the neuronal pathology
associated with the disease. The overall aim of our study was to (i)
investigate the spatio-temporal localization and expression analysis of
spatacsin in different cell types available (ii) to recapitulate early
neurodevelopmental deficits at the cortical neural progenitor cells
(NPCs) stage, and (iii) to delineate the neurodegenerative phenotype and
slowly progressive cortical degeneration in terminally differentiated
neurons.
We show here, preferential expression of spatacsin in human neurons,
particularly in cortical projection neurons. Importantly, spatacsin is
temporally expressed all throughout neuronal differentiation and
maturation. Our NPC model evidenced, widespread transcriptional
alterations in neurodevelopmental pathways, associated with proliferation
deficit and impaired cortical neurogenesis. Interestingly, these early
developmental phenotypes were rescued by GSK3 modulation. Examination of
terminally differentiated neurons from SPG11 patients revealed axonal
degeneration, impaired vesicular transport and reduced neuritic
complexity.
In conclusion, our human iPSC model reveals a novel temporal scenario for
SPG11: early onset proliferation and neurogenesis anomalies during
cortical development (in first two decades), mimicking a TCC and cortical
atrophy. Progressive axonal degeneration, in the ensuing decades, results
in impaired axonal transport, with the clinical correlates of spastic
paraparesis and peripheral neuropathy. Furthermore, this in-vitro model
offers an ideal platform to screen novel therapeutic compounds for an
intervention during early disease stages, thereby paving the road to
discover new treatment strategies for SPG11 related HSPs.
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