Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Chang, Jaerak; Lee, Seongju; Blackstone, Craig

doi:10.1172/jci77598

Cited by 187 publications

(261 citation statements)

References 42 publications

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“…Moreover, spastizin and spatacsin were essential for the initiation of lysosomal tabulation, and their loss resulted in depletion of free lysosomes, competent to fuse with autophagosomes, and a resultant accumulation of autolysosomes, reflecting a failure in autophagic lysosome reformation [58]. These results are consistent with recent findings in fibroblasts from SPG11 and SPG15 patients, of selective enlargement of LAMP1-positive structures, and endolysosomal abnormalities, and support a converging mechanism for the two disorders that links dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration [59,60]. …”

Section: Discussionsupporting

confidence: 78%

Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Fraidakis¹,

Brunetti

Blackstone

et al. 2016

Neurodegener Dis

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SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the ‘ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature.

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Section: Discussionsupporting

confidence: 78%

Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Fraidakis¹,

Brunetti

Blackstone

et al. 2016

Neurodegener Dis

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“…Some exemplary clusters of shared or interacting pathways underlying ASS diseases are: Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ). Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 . Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

“…Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

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Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

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“…It was suggested that axonal defects were observed in patients with nonsense and splice variants in SPG11 , which is further supported by a functional study using a mouse model (Pérez-Brangulí et al 2014). Loss of Spatacsin also causes accumulation of autolysosomes and deprivation of free lysosomes, thereby disrupting the autophagic lysosome reformation pathway, ultimately leading to neurodegeneration (Chang et al 2014). In this study, we have identified compound heterozygous variants in SPG11 that were predicted to cause truncation of the corresponding protein.…”

Section: Resultsmentioning

confidence: 99%

“…Onset time is childhood to early adult (Shibasaki et al 2000; Casali et al 2004; Winner et al 2004; Olmez et al 2006; Hehr et al 2007). A majority of SPG11 cases are caused by homozygous recessive or compound heterozygous variants in the SPG11 gene (Stevanin et al 2007, 2008), which codes for the Spatacsin protein with a role in axonal maintenance, cargo trafficking (Pérez-Brangulí et al 2014), and autophagy (Chang et al 2014). Because of overlapping phenotypes in different hereditary spastic paraplegia (HSP) subtypes (Pensato et al 2014), diagnosis of SPG11 is often supplemented with evidence from molecular genetics testing.…”

Section: Case Presentationmentioning

confidence: 99%

Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in SPG11

Chan

et al. 2016

Cold Spring Harb Mol Case Stud

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Hereditary spastic paraplegias (HSPs) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of HSP subtypes, next-generation sequencing is often used to provide supporting evidence. In this study, we report the case of two probands from the same family with HSP symptoms, including bilateral lower limb weakness, unsteady gait, cognitive decline, dysarthria, and slurring of speech since the age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for variants in the SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) variant and the novel maternally inherited c.2316+5G>A splice-donor region variant. Variants in SPG11 are the common cause of autosomal recessive spastic paraplegia type 11. According to the ClinVar database, there are already 101 reported pathogenic variants in SPG11 that are associated with HSPs. To our knowledge, this is the first report of SPG11 variants in our local population. The novel splice variant identified in this study enriches the catalog of SPG11 variants, potentially leading to better genetic diagnosis of HSPs.

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Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Cited by 187 publications

References 42 publications

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Novel Compound Heterozygous <b><i>Spatacsin</i></b> Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in SPG11

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