Sensory neuronopathies: new genes, new antibodies and new concepts

2021 ◽  
Vol 92 (4) ◽  
pp. 398-406 ◽  
Author(s):  
Guillaume Fargeot ◽  
Andoni Echaniz-Laguna
Keyword(s):  
Cerebellar Ataxia ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich Ataxia ◽  
Special Focus ◽  
Diagnostic Strategy ◽  
Sensory Abnormalities ◽  
New Genes ◽  
New Concepts ◽  
User Friendly

Degeneration of dorsal root ganglia (DRG) and its central and peripheral projections provokes sensory neuronopathy (SN), a rare disorder with multiple genetic and acquired causes. Clinically, patients with SN usually present with proprioceptive ataxia, patchy and asymmetric sensory abnormalities, widespread areflexia and no weakness. Classic causes of SN include cancer, Sjögren’s syndrome, vitamin deficiency, chemotherapy, mitochondrial disorders and Friedreich ataxia. More recently, new genetic and dysimmune disorders associated with SN have been described, including RFC1 gene-linked cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and anti-FGFR3 antibodies. In this review, we detail the pathophysiology of DRG degeneration, and the genetic and acquired causes of SN, with a special focus on the recently described CANVAS and anti-FGFR3 antibodies. We also propose a user-friendly and easily implemented SN diagnostic strategy.

scholarly journals Friedreich ataxia: metal dysmetabolism in dorsal root ganglia (651.1)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Joseph Mazurkiewicz ◽  
R Liane Ramirez ◽  
Arnulf Koeppen
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich Ataxia

scholarly journals Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

2020 ◽  
Author(s):  
E. Britti ◽  
F. Delaspre ◽  
M. Medina-Carbonero ◽  
A. Sanz ◽  
M. Llovera ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Apoptotic Cell ◽  
Primary Cultures ◽  
Active Form ◽  
Friedreich Ataxia ◽  
Mitochondrial Protein ◽  
Drg Neurons ◽  
Dorsal Root Ganglia Neurons ◽  
Neurite Degeneration

ABSTRACTFriedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential. Accordingly, apoptotic markers and neurite degeneration are reduced resulting in cell survival recovery with calcitriol supplementation. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

scholarly journals In vivo survival and differentiation of Friedreich ataxia iPSC ‐derived sensory neurons transplanted in the adult dorsal root ganglia

2021 ◽  
Author(s):  
Serena Viventi ◽  
Stefano Frausin ◽  
Sara E. Howden ◽  
Shiang Y. Lim ◽  
Rocio K. Finol‐Urdaneta ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich Ataxia

scholarly journals Friedreich ataxia: metal dysmetabolism in dorsal root ganglia

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Arnulf H Koeppen ◽  
Erik C Kuntzsch ◽  
Sarah T Bjork ◽  
R Liane Ramirez ◽  
Joseph E Mazurkiewicz ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich Ataxia

scholarly journals Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

2019 ◽  
Author(s):  
Chiara Dionisi ◽  
Myriam Rai ◽  
Marine Chazalon ◽  
Serge N. Schiffmann ◽  
Massimo Pandolfo
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Cell Model ◽  
Systemic Disease ◽  
Friedreich Ataxia ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Relative Contribution ◽  
Gaa Repeats ◽  
Induced Pluripotent

AbstractHuman induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA).FRDA is a recessive neurodegenerative and systemic disease due to epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus. The most characteristic early neuropathologic finding in FRDA is the loss of large primary proprioceptive neurons in the dorsal root ganglia (DRGs), with associated loss of large myelinated fibers in the dorsal roots and in the posterior columns of the spinal cord. Both a developmental deficit and progressive neurodegeneration are thought to underlie the loss of proprioceptors in FRDA, though the relative contribution of these two components is unclear. The basis of the high specific vulnerability of proprioceptors in FRDA is also unknown. In order to address these open questions about FRDA pathogenesis and at the same time develop a cell model that can be applied to other conditions primarily affecting proprioceptors, we set up a protocol to differentiate iPSCs into primary proprioceptive neurons. We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.

scholarly journals Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia

2017 ◽  
pp. nlw111 ◽  
Author(s):  
Arnulf H. Koeppen ◽  
Alyssa B. Becker ◽  
Jiang Qian ◽  
Paul J. Feustel
Keyword(s):  
Spinal Cord ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Friedreich Ataxia

scholarly journals Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

2020 ◽  
Author(s):  
Elena Britti ◽  
Fabien Delaspre ◽  
Arabela Sanz ◽  
Marta Medina-Carbonero ◽  
Marta Llovera ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Mitochondrial Function ◽  
Dorsal Root ◽  
Primary Cultures ◽  
Active Form ◽  
Friedreich Ataxia ◽  
Mitochondrial Protein ◽  
Drg Neurons ◽  
Dorsal Root Ganglia Neurons ◽  
Neurite Degeneration

Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

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