Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration

Pozner, Tatyana; Regensburger, Martin; Engelhorn, Tobias; Winkler, Jürgen; Winner, Beate

doi:10.1093/brain/awaa099

Cited by 27 publications

(26 citation statements)

References 76 publications

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“…Previous studies reported an accumulation of autophagosomes in SPG11, due to a deficit in autophagolysosome reformation ( Renvoisé et al, 2014 ; Branchu et al, 2017 ; Vantaggiato et al, 2019 ; Pozner et al, 2020 ; Khundadze et al, 2021 ). Ultrastructural analysis of SPG11 MNs confirmed this finding, revealing presence of neuritic electron-dense aggregates in SPG11, but not in control MN neurites which exhibited small electron dense lipofuscin particles only ( Figures 2C,D and Supplementary Figure 2C ).…”

Section: Resultsmentioning

confidence: 91%

“…Mitochondrial dysfunction and impaired transport of mitochondria have been implicated in various neurodegenerative diseases including Charcot-Marie Tooth 2A and Parkinson's (Kitada et al, 1998;Palacino et al, 2004;Lezi and Swerdlow, 2012;Stevens et al, 2015;Rizzo et al, 2016;Prots et al, 2018). Interestingly, increasing evidence supports a specific vulnerability of dopaminergic neurons in SPG11 (Paisan-Ruiz et al, 2010;Guidubaldi et al, 2011;Faber et al, 2018b;Pozner et al, 2020).…”

Section: Overlapping Disease Mechanisms In Spg11 and Spg15mentioning

confidence: 99%

“…HSPs can be classified as either pure or complicated ( Harding, 1983 ). Complicated forms are defined by the presence of additional symptoms, including intellectual disability, thin corpus callosum, seizures, ataxia, and peripheral neuropathy ( Harding, 1983 ; Giudice et al, 2014 ; Schüle et al, 2016 ; Pozner et al, 2020 ). More than 72 genes and loci underlying HSP have been identified to date.…”

Section: Introductionmentioning

confidence: 99%

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Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

et al. 2021

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Pathogenic variants in SPG11 are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs. To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11. Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs.

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Section: Resultsmentioning

confidence: 91%

Section: Overlapping Disease Mechanisms In Spg11 and Spg15mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

et al. 2021

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“…However, miglustat poorly crosses the blood–brain barrier and it would be informative to test whether an alternative strategy to decrease ganglioside levels in the brains of Spg11 knockout mice can improve the motor or cognitive symptoms that have been observed 86 . As SPG11 patients generally present their first symptoms before 10 years of age, it has been proposed that aside from neurodegeneration, altered brain development may contribute to the disease 87 . Consistent with this hypothesis, models derived from induced pluripotent stem cells of SPG11 patients show reduced proliferation of neuronal progenitors, impaired neurogenesis, and impaired neuronal differentiation 88 , 89 .…”

Section: Management Of Hspmentioning

confidence: 99%

Recent advances in understanding hereditary spastic paraplegias and emerging therapies

Lallemant-Dudek¹,

Darios²,

Dürr³

2021

Fac Rev

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Hereditary spastic paraplegias (HSPs) are a group of rare, inherited, neurological diseases characterized by broad clinical and genetic heterogeneity. Lower-limb spasticity with first motoneuron involvement is the core symptom of all HSPs. As spasticity is a syndrome and not a disease, it develops on top of other neurological signs (ataxia, dystonia, and parkinsonism). Indeed, the definition of genes responsible for HSPs goes beyond the 79 identified SPG genes. In order to avoid making a catalog of the different genes involved in HSP in any way, we have chosen to focus on the HSP with cerebellar ataxias since this is a frequent association described for several genes. This overlap leads to an intermediary group of spastic ataxias which is actively genetically and clinically studied. The most striking example is SPG7 , which is responsible for HSP or cerebellar ataxia or both. There are no specific therapies against HSPs, and there is a dearth of randomized trials in patients with HSP, especially on spasticity when it likely results from other mechanisms. Thus far, no gene-specific therapy has been developed for HSP, but emerging therapies in animal models and neurons derived from induced pluripotent stem cells are potential treatments for patients.

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“…HSPs are characterized by spasticity and weakness of hip and leg muscles that are caused by axonal degeneration of cortical motor neurons. HSP patientspecific iPSC lines were generated for multiple form of HSP including SPG4 [116,117], SPG3A [118], SPG11 [119,120], SPG15 and SPG48 [121]. By knocking in disease-related mutations using gene editing, disease-specific phenotypes were recapitulated, providing additional models to study HSPs [122].…”

Section: Other Motor Neuron Diseasesmentioning

confidence: 99%

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

Karpe

Chen

2021

Pharmaceuticals

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Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.

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Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration

Cited by 27 publications

References 76 publications

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons

Recent advances in understanding hereditary spastic paraplegias and emerging therapies

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

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