Neurotransmitter abnormalities and response to supplementation in SPG11

Vanderver, Adeline; Tonduti, Davide; Auerbach, Sarah; Schmidt, Johanna L.; Parikh, Sumit; Gowans, Gordon C.; Jackson, Kelly E.; Brock, Pamela; Patterson, Marc C.; Nehrebecky, Michelle; Godfrey, Rena A.; Zein, Wadih M.; Gahl, William A.; Toro, Camilo

doi:10.1016/j.ymgme.2012.05.020

Cited by 17 publications

(30 citation statements)

References 18 publications

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“…Control siRNAs were from Ambion. All primary human cell lines have been described previously (13,41); SPG11-1, SPG11-2, and SPG11-3 cell lines were provided by William Gahl (NIH, Bethesda, Maryland, USA), Camilo Toro (NIH, Bethesda, Maryland, USA), and Adeline Vanderver (Children's National Medical Center, Washington, DC, USA). Lysates were clarified by centrifugation (15,700 g, 4 °C) for 15 minutes, and supernatants were incubated with 0.5 μg of antibodies at 4°C for 16 hours, followed by incubation with Protein A/G PLUS-agarose (Santa Cruz Biotechnology) for 2 hours.…”

Section: Methodsmentioning

confidence: 99%

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Chang¹,

Lee²,

Blackstone³

2014

J. Clin. Invest.

187

230

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Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Chang¹,

Lee²,

Blackstone³

2014

J. Clin. Invest.

187

230

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“…These forms comprise almost one third of recessive complex HSP cases, with ~70% of these resulting from mutations in either SPG15 / ZFYVE26 (MIM# 270700) or SPG11/KIAA1840 (MIM# 604360). Both disorders can also present with retinal or lenticular abnormalities, and they are often associated with cognitive impairment as well as prominent juvenile parkinsonism that can be responsive to dopaminergic therapy . Cerebellar findings including ataxia and impaired extraocular muscle movements are also commonly observed.…”

Section: Introductionmentioning

confidence: 99%

“…Spatacsin also has an N‐terminal, β‐propeller‐like domain, and spastizin harbors a zinc‐binding FYVE (present in Fab1, YOTB, Vac1, and EEA1) domain. Spastizin has been localized to different and often disparate intracellular locations in various studies . Similarly, proposed functions vary broadly and include cytokinesis, DNA repair, late endosomal/lysosomal trafficking, and autophagy .…”

Section: Introductionmentioning

confidence: 99%

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Renvoisé

Chang

Singh

et al. 2014

Ann Clin Transl Neurol

Self Cite

101

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ObjectiveHereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 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.MethodsWe describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 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.ResultsFibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent.InterpretationEmerging 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 SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs 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.

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“…These neurotransmitter conditions are the reason all children with unexplained dystonia or akinesia should have a l ‐dopa trial, particularly in the context of a normal MRI and suggestive clinical features, as above. Complete dopa responsiveness is suggestive of a primary neurotransmitter condition and sometimes other monogenic disorders such as PARKIN deletions; however, varying dopamine responsiveness can be observed in some other genetic nonprogressive disorders (DNAJC12, DYT11, paroxyxmal kinesigenic and nonkinesigenic dyskinesia, and pyruvate dehydrogenase complex deficiency), genetic‐progressive disorders (ataxia telangiectasia, chorea acanthocytosis, DJ‐1, FBX07, Kufor‐Rakeb disease, nuclear inclusion body disease, PINK1, pantothenate kinase associated neurodegeneration, PLA2G6 associated neurodegeneration, pontocerebellar hypoplasia type 2, SCA2, SCA3, SOX6, SPG11, and xeroderma pigmentosum), and, to a lesser extent, in acquired disorders such as movement disorders with lupus, organophosphate poisoning, subacute sclerosing panencephalitis, postencephalitic dystonia, or extrapontine myelinolysis. The role of l ‐dopa in management of dystonic cerebral palsy (CP) is questionable and results from previous studies are contradictory …”

Section: Symptomatic Therapiesmentioning

confidence: 99%

Current therapies and therapeutic decision making for childhood‐onset movement disorders

2019

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Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early‐onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease‐modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease‐modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha‐adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of “disease‐specific” therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood‐onset movement disorders. © 2019 International Parkinson and Movement Disorder Society

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Neurotransmitter abnormalities and response to supplementation in SPG11

Cited by 17 publications

References 18 publications

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Lysosomal abnormalities in hereditary spastic paraplegia types SPG 15 and SPG 11

Current therapies and therapeutic decision making for childhood‐onset movement disorders

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