Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions

Abstract

The most common form of autosomal recessive hereditary spastic paraplegia is caused by mutations in the SPG11/KIAA1840 gene on chromosome 15q. The nature of the vast majority of SPG11 mutations found to date suggests a loss-of-function mechanism of the encoded protein, spatacsin. The SPG11 phenotype is, in most cases, characterized by a progressive spasticity with neuropathy, cognitive impairment and a thin corpus callosum on brain MRI. Full neuropathological characterization has not been reported to date despite the description of >100 SPG11 mutations. We describe here the clinical and pathological features observed in two unrelated females, members of genetically ascertained SPG11 families originating from Belgium and Italy, respectively. We confirm the presence of lesions of motor tracts in medulla oblongata and spinal cord associated with other lesions of the central nervous system. Interestingly, we report for the first time pathological hallmarks of SPG11 in neurons that include intracytoplasmic granular lysosome-like structures mainly in supratentorial areas, and others in subtentorial areas that are partially reminiscent of those observed in amyotrophic lateral sclerosis, such as ubiquitin and p62 aggregates, except that they are never labelled with anti-TDP-43 or anti-cystatin C. The neuropathological overlap with amyotrophic lateral sclerosis, associated with some shared clinical manifestations, opens up new fields of investigation in the physiopathological continuum of motor neuron degeneration.

Keywords: amyotrophic lateral sclerosis; lipofuscin; lysosome; spastic paraplegia 11; spatacsin.

The most common autosomal recessive spastic paraplegia is caused by mutations in SPG11. Denora et al. report the first postmortem neuropathological analysis of two unrelated patients with SPG11, and demonstrate clinical and pathological overlap between this disease and ALS. Abnormal neuronal lipid accumulation is identified as a hallmark of SPG11.

Figure 1

Neuronal rarefactions and presence of inclusions in the hypoglossal nucleus of Patient BG-2. Similar features were observed in remaining neurons of the anterior horns of the spinal cord (data not shown). Large eosinophilic inclusions are observed in the neuronal perikarya (arrows) after haematoxylin and eosin (A) or Klüver-Barrera (B, blue) staining. Numerous inclusions (arrows) are immunoreactive for ubiquitin (C) or p62 (D). No labelling of the inclusions was evidenced with an anti-TDP-43 (E) or an anti-cystatin C antibody (F). Scale bars = 50 µm.

Figure 2

Spinal ganglion of Patient BG-2. Haematoxylin and eosin staining highlighted large, mostly eosinophilic inclusions in the perikarya of the ganglion cell neurons (A, arrows). Similar irregular inclusions were observed in the neuronal perikarya by Klüver-Barrera staining (B, arrows) or by an anti-ubiquitin (C) or and anti-p62 (D) antibody immunolabelling. The inclusions were not labelled by an anti-TDP-43 antibody (E, arrows). Giant bodies or ‘retention bodies’ (arrows) were observed at electron microscopy of a ganglion cell (F, low magnification; G, high magnification of a giant body). Classical lipofuscin granules were also present in these giant bodies (H). Scale bars: immunohistochemistry = 50 µm; electron microscopy = 1 µm.

Figure 3

Electron micrographs of a motor neuron of the anterior horn of the lumbosacral spinal cord. (A) Presence of electron-lucent zones (arrows) intermingled with lipofuscin. The area indicated by the horizontal arrow in (A) is shown at a higher magnification in (B, arrows).