Friedreich’s Ataxia: From the (GAA) n Repeat Mediated Silencing to New Promising Molecules for Therapy

Marmolino, Daniele; Acquaviva, Fabio

doi:10.1007/s12311-008-0084-2

Cited by 33 publications

(31 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have observed PGC-1α down-regulation also in neural precursor cells from the subventricular zone of these animals, and in fibroblasts and lymphoblastoid cell lines from FRDA patients [37], [38]. PGC-1α is a multifunctional protein found at higher levels in tissues with high metabolic requirement such as brown fat, skeletal muscle, kidney, heart, and brain [39]–[41], that functions as a coactivator to most nuclear receptors and to several other transcription factors [42].…”

Section: Introductionmentioning

confidence: 72%

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

et al. 2010

Self Cite

View full text Add to dashboard Cite

BackgroundCells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models.Methodology/Principal FindingsWe used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1α. Compared to control cells, PGC-1α and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1α direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1α activation with the PPARγ agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord.Conclusions/SignificancePGC-1α down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARγ agonists, suggesting a potential therapeutic approach for FRDA.

show abstract

Section: Introductionmentioning

confidence: 72%

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Reductions in PGC-1α have been observed in brain and muscle from patients with Huntington Disease (Cui et al, 2006; Weydt et al, 2006; Chaturvedi et al, 2009), potentially due to pathogenic interactions of mutant huntingtin with transcriptional regulators of PGC-1α (Cui et al, 2006). In addition, PGC-1α may be involved in the pathologies of Alzheimer’s Disease (Qin et al, 2009) and Friedreich’s Ataxia (Marmolino and Acquaviva, 2009). However, given its developmental regulation, we hypothesized that analyses of GABAergic gene expression and function during the first month of life in PGC-1α −/− mice would reveal primary downstream targets for PGC-1α in the brain.…”

Section: Introductionmentioning

confidence: 99%

Parvalbumin Deficiency and GABAergic Dysfunction in Mice Lacking PGC-1α

Lucas¹,

Markwardt²,

et al. 2010

View full text Add to dashboard Cite

The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) is a master regulator of metabolism in peripheral tissues, and it has been proposed that PGC-1␣ plays a similar role in the brain. Recent evidence suggests that PGC-1␣ is concentrated in GABAergic interneurons, so we investigated whether male and female PGC-1␣ Ϫ/Ϫ mice exhibit abnormalities in interneuron gene expression and/or function. We found a striking reduction in the expression of the Ca 2ϩ -binding protein parvalbumin (PV), but not other GABAergic markers, throughout the cerebrum in PGC-1␣ ϩ/Ϫ and Ϫ/Ϫ mice. Furthermore, PGC-1␣ overexpression in cell culture was sufficient to robustly induce PV expression. Consistent with a reduction in PV rather than a loss of PV-expressing interneurons, spontaneous synaptic inhibition was not altered in PGC-1␣ Ϫ/Ϫ mice. However, evoked synaptic responses displayed less paired-pulse depression and dramatic facilitation in response to repetitive stimulation at the gamma frequency. PV transcript expression was also significantly reduced in retina and heart of PGC-1␣ Ϫ/Ϫ animals, suggesting that PGC-1␣ is required for proper expression of PV in multiple tissues. Together these findings indicate that PGC-1␣ is a novel regulator of interneuron gene expression and function and a potential therapeutic target for neurological disorders associated with interneuron dysfunction.

show abstract

“…The myohaptic technology opens new perspectives to understand the pathogenesis of motion deficits in neurological patients. Given the rapid development of new therapies for neurological disorders which were considered as not curable a decade ago [29–31], there is a growing need for clinically-oriented standardized tools for the monitoring of neurological patients with movement disorders.…”

Section: Discussionmentioning

confidence: 99%

A New Myohaptic Instrument to Assess Wrist Motion Dynamically

Manto¹,

Braber

Grimaldi

et al. 2010

Sensors

View full text Add to dashboard Cite

The pathophysiological assessment of joint properties and voluntary motion in neurological patients remains a challenge. This is typically the case in cerebellar patients, who exhibit dysmetric movements due to the dysfunction of cerebellar circuitry. Several tools have been developed, but so far most of these tools have remained confined to laboratories, with a lack of standardization. We report on a new device which combines the use of electromyographic (EMG) sensors with haptic technology for the dynamic investigation of wrist properties. The instrument is composed of a drivetrain, a haptic controller and a signal acquisition unit. Angular accuracy is 0.00611 rad, nominal torque is 6 N·m, maximal rotation velocity is 34.907 rad/sec, with a range of motion of −1.0472 to +1.0472 rad. The inertia of the motor and handgrip is 0.004 kg·m2. This is the first standardized myohaptic instrument allowing the dynamic characterization of wrist properties, including under the condition of artificial damping. We show that cerebellar patients are unable to adapt EMG activities when faced with an increase in damping while performing fast reversal movements. The instrument allows the extraction of an electrophysiological signature of a cerebellar deficit.

show abstract

Friedreich’s Ataxia: From the (GAA) n Repeat Mediated Silencing to New Promising Molecules for Therapy

Cited by 33 publications

References 125 publications

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

Parvalbumin Deficiency and GABAergic Dysfunction in Mice Lacking PGC-1α

A New Myohaptic Instrument to Assess Wrist Motion Dynamically

Contact Info

Product

Resources

About