Biology

Hereditary spastic paraplegia (hsp) is a genetically heterogeneous group of disorders that commonly affect the long fibers of the corticospinal tract and posterior columns in the spinal cord, leading to progressive gait disturbances with muscle weakness and spasticity (salinas et al., 2008). more than 40 gene loci are associated with hsp, which may be autosomal dominant, recessive or x-linked recessive. mutations in spg4/spast account for the largest group of adult-onset hsp cases and about 40-44% of all autosomal- dominant ‘uncomplicated’ hsp (i.e. without other signs such as ataxia, dementia or retardation) (salinas et al., 2008; vandebona et al., 2012). spastin, the protein encoded by spast , is a member of the aaa (atpases associated with diverse cellular activities) group of proteins, which are involved in cell cycle regulation, protein degradation, organelle biogenesis and vesicle-mediated functions (roll-mecak and mcnally, 2010). spastin is involved with microtubule disassembly (errico et al., 2002) and is enriched in the distal axon of corticospinal motor neurons (reviewed in salinas et al., 2007), the degeneration of which is seen post-mortem in the spinal cords of hsp patients, histologically (deluca et al., 2004) and after magnetic imaging (hedera et al., 2005). the cellular mechanisms whereby mutations cause axon degeneration are not understood but spastin mutations cause disrupted axonal transport (mcdermott et al., 2003; molon et al., 2004). consistent with these findings, spg4 mutant mice had gait abnormalities, axonal swellings in cortical axons in vitro and reduced anterograde axonal transport of mitochondria and β-amyloid precursor protein (app)-containing membrane bound organelles (kasher et al., 2009). overexpression of mutated in hek293 cells led to increased perinuclear distribution of mitochondria and peroxisomes (mcdermott et al., 2003). until now, functions of spastin and mutated spastin have been identified , by over- or underexpression in human and animal cell lines, and in genetically modified mouse and drosophila models. although instructive, these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease and that presumably underlie the variable clinical outcome. central questions remain concerning the cellular consequences of mutations and how these cause an adult- onset disease, with variable severity and age of onset, affecting mainly the long axons of the corticospinal tract. to address these issues, we developed a new patient-derived stem cell model for hsp, based on neural progenitors from the organ of smell in the nose. these cells are generated from biopsies of olfactory mucosa (féron et al., 1998) grown in defined medium to produce multipotent neural progenitors (murrell et al., 2005) and then propagated as adherent cultures (olfactory neurosphere-derived, ons, cells) (matigian et al., 2010). ons cells are standardized cell populations grown under strict quality assurance such that technical

sp_admin / 8th October 2022

HIGHLIGHTS who: Greger Abrahamsen and colleagues from the Participants and nasal biopsies HSP patients were reviewed and examined by a

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