Open AccessLysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11
Author(s) -
Renvoisé Benoît,
Chang Jaerak,
Singh Rajat,
Yonekawa Sayuri,
FitzGibbon Edmond J.,
Mankodi Ami,
Vanderver Adeline,
Schindler Alice B.,
Toro Camilo,
Gahl William A.,
Mahuran Don J.,
Blackstone Craig,
Pierson Tyler Mark
Publication year - 2014
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.64
Subject(s) - hereditary spastic paraplegia , parkinsonism , lamp1 , endosome , endoplasmic reticulum , medicine , tardbp , phenotype , microbiology and biotechnology , pathology , biology , genetics , gene , disease , dementia , intracellular , frontotemporal dementia
Objective Hereditary spastic paraplegias ( HSP s) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified ( SPG 1‐71) to date. SPG 15 and SPG 11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early‐onset parkinsonism. Methods We describe two new cases of SPG 15 and investigate cellular changes in SPG 15 and SPG 11 patient‐derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes. Results Fibroblasts prepared from patients with SPG 15 have selective enlargement of LAMP 1‐positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP 1‐positive structures was also observed in cells from multiple SPG 11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG 15 protein spastizin/ ZFYVE 26 and the SPG 11 protein spatacsin were interdependent. Interpretation Emerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP ‐5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26 −/− mice revealed a similar phenotype to human SPG 15, and cells in these mice had endolysosomal abnormalities. SPG 15 and SPG 11 are particularly notable among HSP s because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.