Giant Axonal Neuropathy

Dubeau, F.; Michaud, Johan; Lamarre, Louis

doi:10.1097/00005072-198505000-00153

Cited by 11 publications

(7 citation statements)

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“…RFs were concentrated in astrocyte endfeet around blood vessels (Fig.1A) and dispersed in cerebellar white matter in proximity to giant axonal swellings (Fig.1B) . These data clearly demonstrate that KLHL16 loss-of-function mutation leads to astrocytes acquiring marked histopathologic features, in agreement with early neuropathologic observations in GAN (5, 6, 19–21). In order to examine the mechanistic link between KLHL16 /gigaxonin downregulation and/or dysfunction and astrocytopathy, we reprogrammed seven skin fibroblast lines from GAN patients with different KLHL16 mutations (Fig.1C; Supplemental Fig.1) to iPSCs.…”

Section: Resultssupporting

confidence: 90%

“…We did not observe major differences in lamin-A/C and B1 expression (Fig.2A) or Lamin B1 localization (Supplemental Fig.3) in the parental line versus the isogenic control cells. However, by immunoblot we observed variable vimentin expression, such that four patient lines (2, 5, 6, 7) expressed detectable levels of vimentin (Vim + ), while the remaining patient lines (1,3,4) did not (Vim - ), similar to the 15CA non-GAN control and the patient 7 isogenic clones (Fig. 2A) .…”

Section: Resultsmentioning

confidence: 77%

“…Death nearly always occurs by the third decade. The clinical findings and pathologic distribution of lesions in GAN are consistent with a central-peripheral distal axonopathy (5, 6).…”

Section: Introductionmentioning

confidence: 61%

“…To date, most attention has been directed at IF aggregates within GAN neurons and far less attention has been directed at IF aggregates within GAN astrocytes. Despite the fact that conspicuous and abundant IF aggregates within astrocytes are described in every reported autopsy case of GAN (5,6,(19)(20)(21), the contribution of astrocyte dysfunction to neurodegeneration and the pathogenesis of astrocyte IF aggregation remain underinvestigated.…”

Section: Introductionmentioning

confidence: 99%

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Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

Battaglia

Faridounnia

Beltran

et al. 2023

Preprint

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Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed significant involvement of astrocytes in GAN. To study the underlying cellular mechanisms, we generated human models of GAN using induced pluripotent stem cells (iPSCs). Skin fibroblasts from seven GAN patients carrying different KLHL16 mutations were reprogrammed to iPSCs, and isogenic controls were derived via CRISPR/Cas9 editing. Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic clones. While GAN iPSCs displayed normal organization of lamin B1 and keratin IFs, they exhibited patient-specific increased expression and perinuclear bundling of vimentin. Nestin IF morphology was unaffected, but fewer nestin-positive cells were present in GAN NPCs compared to controls. The most dramatic phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which displayed dense perinuclear IF accumulations and abnormal nuclear morphology. GFAP oligomerization and perinuclear aggregation were strongly potentiated in the presence of vimentin, and GAN cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 77%

“…Death nearly always occurs by the third decade. The clinical findings and pathologic distribution of lesions in GAN are consistent with a central-peripheral distal axonopathy (5, 6).…”

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

Battaglia

Faridounnia

Beltran

et al. 2023

Preprint

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show abstract

“…Death nearly always occurs by the third decade. The clinical findings and pathologic distribution of lesions in GAN are consistent with a central-peripheral distal axonopathy ( Dubeau et al ., 1985 ; Thomas et al ., 1987 ).…”

Section: Introductionmentioning

confidence: 75%

Intermediate filament dysregulation in astrocytes in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN)

Battaglia,

Faridounnia,

Beltran

et al. 2023

MBoC

View full text Add to dashboard Cite

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, which regulates intermediate filament (IF) turnover. Previous neuropathological studies and examination of postmortem brain tissue in the current study revealed involvement of astrocytes in GAN. To develop a clinically-relevant model, we reprogrammed skin fibroblasts from seven GAN patients to pluripotent stem cells (iPSCs), which were used to generate neural progenitor cells (NPCs), astrocytes, and brain organoids. Multiple isogenic control clones were derived via CRISPR/Cas9 gene editing of one patient line carrying the G332R gigaxonin mutation. All GAN iPSCs were deficient for gigaxonin and displayed patient-specific increased vimentin expression. GAN NPCs had lower nestin expression and fewer nestin-positive cells compared to isogenic controls, but nestin morphology was unaffected. GAN brain organoids were marked by the presence of neurofilament and GFAP aggregates. GAN iPSC-astrocytes displayed striking dense perinuclear vimentin and GFAP accumulations and abnormal nuclear morphology. In over-expression systems, GFAP oligomerization and perinuclear aggregation were augmented in the presence of vimentin. GAN patient cells with large perinuclear vimentin aggregates accumulated significantly more nuclear KLHL16 mRNA compared to cells without vimentin aggregates. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.

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Genetically Determined Neuropathies

Bilbao

Schmidt

2014

Biopsy Diagnosis of Peripheral Neuropathy

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Giant Axonal Neuropathy

Cited by 11 publications

References 0 publications

Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

Intermediate filament dysregulation in astrocytes in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN)

Genetically Determined Neuropathies

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