title: The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene.
abstract: Hereditary spastic paraparesis (HSP) is a genetically heterogeneous disorder, the most common cause of which is mutation of the spastin gene. Recent evidence suggests a role for spastin in microtubule dynamics, but the distribution of the protein within the CNS is unknown. The core neuropathology of HSP is distal degeneration of the lateral corticospinal tract and of fasciculus gracilis, but there are few neuropathological studies of cases with a defined mutation. We aimed to determine the distribution of spastin expression in the human CNS and to investigate the cellular pathology of the motor system in HSP due to mutation of the spastin gene. Using an antibody to spastin, we have carried out immunohistochemistry on postmortem brain. We have demonstrated that spastin is a neuronal protein. It is widely expressed in the CNS so that the selectivity of the degeneration in HSP is not due to the normal cellular distribution of the protein. We have identified mutation of the spastin gene in 3 autopsy cases of HSP. Distal degeneration of long tracts in the spinal cord, consistent with a dying back axonopathy, was accompanied by a microglial reaction. The presence of novel hyaline inclusions in anterior horn cells and an alteration in immunostaining for cytoskeletal proteins and mitochondria indicates that long tract degeneration is accompanied by cytopathology in the motor system and may support a role for derangement of cytoskeletal function. All 3 cases also demonstrated evidence of tau pathology outside the motor system, suggesting that the neuropathology is not confined to the motor system in spastin-related HSP.
authors.affiliation: Academic Unit of Pathology, University of Sheffield, Sheffield, United Kingdom. s.wharton@sheffield.ac.uk
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDermott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grierson
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wood
authors.forename: Catherine
authors.initials: C
authors.lastname: Gelsthorpe
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000251:Adenosine Triphosphatases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004252:DNA Mutational Analysis; D004525:Efferent Pathways / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D006818:Hyalin / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D020336:Paraparesis, Spastic / Q000235:genetics* / Q000473:pathology*; D000074181:Spastin; D013116:Spinal Cord / Q000473:pathology; D051843:Synucleins; D014404:Tubulin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000251:Adenosine Triphosphatases; D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D000074181:Spastin; D051843:Synucleins; D014404:Tubulin; D025801:Ubiquitin; D016875:tau Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C400283:SPAST protein, human