PMID- 33708070
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210313
IS  - 1662-4548 (Print)
IS  - 1662-453X (Electronic)
IS  - 1662-453X (Linking)
VI  - 15
DP  - 2021
TI  - Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical 
      Symptoms in Friedreich's Ataxia: Clues of an "Out-Brain Origin" of the Disease 
      From a Family Study.
PG  - 638810
LID - 10.3389/fnins.2021.638810 [doi]
LID - 638810
AB  - Friedreich's ataxia (FRDA) is the most frequent autosomal recessive ataxia in 
      western countries, with a mean age of onset at 10-15 years. Patients manifest 
      progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal 
      weakness, and other systemic manifestations. Previously, we described a family 
      displaying two expanded GAA alleles not only in the proband affected by 
      late-onset FRDA but also in the two asymptomatic family members: the mother and 
      the younger sister. Both of them showed a significant reduction of frataxin 
      levels, without any disease manifestation. Here, we analyzed if a protective 
      mechanism might contribute to modulate the phenotype in this family. We 
      particularly focused on the transcription factor nuclear factor erythroid 
      2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on 
      the glutathione (GSH) system, an index of reactive oxygen species (ROS) 
      detoxification ability. Our findings show a great reactivity of the GSH system to 
      the frataxin deficiency, particularly in the asymptomatic mother, where the genes 
      of GSH synthesis [glutamate-cysteine ligase (GCL)] and GSSG detoxification [GSH 
      S-reductase (GSR)] were highly responsive. The GSR was activated even in the 
      asymptomatic sister and in the proband, reflecting the need of buffering the GSSG 
      increase. Furthermore, and contrasting the NRF2 expression documented in FRDA 
      tissues, NRF2 was highly activated in the mother and in the younger sister, while 
      it was constitutively low in the proband. This suggests that, also under frataxin 
      depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may 
      contribute to protect against the progressive oxidative damage, helping to 
      prevent the onset of neurological symptoms and highlighting an "out-brain origin" 
      of the disease.
CI  - Copyright (c) 2021 Petrillo, Santoro, La Rosa, Perna, Gallo, Bertini, Silvestri and 
      Piemonte.
FAU - Petrillo, Sara
AU  - Petrillo S
AD  - Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino 
      Gesu, IRCCS, Rome, Italy.
FAU - Santoro, Massimo
AU  - Santoro M
AD  - IRCCS Fondazione Don Carlo Gnocchi ONLUS, Florence, Italy.
FAU - La Rosa, Piergiorgio
AU  - La Rosa P
AD  - Division of Neuroscience, Department of Psychology, Sapienza University of Rome, 
      Rome, Italy.
FAU - Perna, Alessia
AU  - Perna A
AD  - Department of Neurosciences, Universita Cattolica del Sacro Cuore, Rome, Italy.
FAU - Gallo, Maria Giovanna
AU  - Gallo MG
AD  - Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino 
      Gesu, IRCCS, Rome, Italy.
FAU - Bertini, Enrico Silvio
AU  - Bertini ES
AD  - Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino 
      Gesu, IRCCS, Rome, Italy.
FAU - Silvestri, Gabriella
AU  - Silvestri G
AD  - Department of Neurosciences, Universita Cattolica del Sacro Cuore, Rome, Italy.
AD  - UOC of Neurology, Area of Neuroscience, Fondazione Policlinico Universitario A. 
      Gemelli IRCCS, Rome, Italy.
FAU - Piemonte, Fiorella
AU  - Piemonte F
AD  - Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino 
      Gesu, IRCCS, Rome, Italy.
LA  - eng
PT  - Journal Article
DEP - 20210223
PL  - Switzerland
TA  - Front Neurosci
JT  - Frontiers in neuroscience
JID - 101478481
PMC - PMC7940825
OTO - NOTNLM
OT  - Friedreich ataxia
OT  - Nrf2
OT  - glutathione
OT  - neurodegenerative disease
OT  - oxidative stress
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/03/13 06:00
MHDA- 2021/03/13 06:01
PMCR- 2021/01/01
CRDT- 2021/03/12 07:12
PHST- 2020/12/07 00:00 [received]
PHST- 2021/01/22 00:00 [accepted]
PHST- 2021/03/12 07:12 [entrez]
PHST- 2021/03/13 06:00 [pubmed]
PHST- 2021/03/13 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fnins.2021.638810 [doi]
PST - epublish
SO  - Front Neurosci. 2021 Feb 23;15:638810. doi: 10.3389/fnins.2021.638810. 
      eCollection 2021.