Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests

Damián, Juan Pablo; Alberdi, Lucia Vázquez; Canclini, Lucía; Rosso, Gonzalo; Bravo, Silvia Olivera; Martinez, Mariana; Uriarte, Natalia; Ruiz, Paul; Calero, Miguel; Tomaso, María Vittoria Di; Kun, Alejandra

doi:10.3390/biom11040601

Cited by 10 publications

(15 citation statements)

References 97 publications

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“…Overall, in both cellular domains, PMP22 expression was higher in TrJ/+ SCs compared to +/+ SCs. This result is in line, not only with works reporting the existence of cytoplasmic aggregates of PMP22 in TrJ/+ nerves [14,53,66,67] but also in agreement with previous work from our group, which determines PMP22 expression in +/+ and TrJ/+ SCs inside the nucleus [69] (Di Tomaso et al, manuscript under review).…”

Section: Discussionsupporting

confidence: 93%

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

Alberdi¹,

Rosso²,

Velóz³

et al. 2022

Preprint

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Charcot-Marie-Tooth (CMT) syndrome is the most common progressive human motor and sensory peripheral neuropathy. CMT type 1E is a demyelinating neuropathy affecting Schwann cells due to pmp22 mutations, modelized by Trembler-J mice. Curcumin, a natural polyphenol com-pound obtained from turmeric (Curcuma longa), exhibits dose- and time-varying antitumor, antioxidant and neuroprotective properties, however, the neurotherapeutic actions of curcumin still remain elusive. Here, we propose curcumin as a possible natural treatment capable of enhancing cellular detoxification mechanisms, resulting in an improvement of the neurodegenerative Trembler-J phenotype. Using a refined method for obtaining enriched Schwann cell cultures, we evaluated the neurotherapeutic action of low dose curcumin treatment on the PMP22 expression, and on the chaperones (HSF1 and Hsp27) and autophagy/mTOR (HDAC6 and ribosomes) pathways in Trembler-J and wild-type genotypes. In wild-type Schwann cells, the action of cur-cumin resulted in strong stimulation of the chaperone and macroautophagy pathway, whereas the modulation of ribophagy showed a mild effect. However, despite the promising neuroprotective effects for the treatment of neurological diseases, we report (demonstrate?) that the action of cur-cumin in Trembler-J Schwann cells could be impaired due to the irreversible impact of ethanol used as a common curcumin vehicle necessary for administration. These results contribute to expand our still limited understanding of PMP22 biology in neurobiology, and expose the intrinsic lability of the neurodegenerative Trembler-J genotype. Furthermore, they unravel interesting physiological mechanisms of cellular resilience relevant for to the pharmacological treatment of the neurodegenerative Tremble J phenotype with curcumin and ethanol. We conclude that the analysis of the effects of the vehicle itself is an essential and in-escapable step to comprehensibly assess the own effects and full potential of curcumin treatment for therapeutic purposes.

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Section: Discussionsupporting

confidence: 93%

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

Alberdi¹,

Rosso²,

Velóz³

et al. 2022

Preprint

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“…After Doppler imaging, mice were euthanized with a quick cervical dislocation 38 . The brain samples were processed as described by Damián et al 39 . Briefly, after cervical dislocation, brains were immersed in 4 paraformaldehyde (PFA) fixative solution in PHEM buffer (60 mM PIPES, 25 mM HEPES, 10 mM EGTA, 2 mM , adjusted to pH 7.2–7.4 with KOH pellets) for 1 h. at 4 C in an orbital shaker.…”

Section: Methodsmentioning

confidence: 99%

Intensity distribution segmentation in ultrafast Doppler combined with scanning laser confocal microscopy for assessing vascular changes associated with ageing in murine hippocampi

Fialho

Alberdi

Martinez

et al. 2022

Sci Rep

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The hippocampus plays an important role in learning and memory, requiring high-neuronal oxygenation. Understanding the relationship between blood flow and vascular structure—and how it changes with ageing—is physiologically and anatomically relevant. Ultrafast Doppler ($$\mu$$ μ Doppler) and scanning laser confocal microscopy (SLCM) are powerful imaging modalities that can measure in vivo cerebral blood volume (CBV) and post mortem vascular structure, respectively. Here, we apply both imaging modalities to a cross-sectional and longitudinal study of hippocampi vasculature in wild-type mice brains. We introduce a segmentation of CBV distribution obtained from $$\mu$$ μ Doppler and show that this mice-independent and mesoscopic measurement is correlated with vessel volume fraction (VVF) distribution obtained from SLCM—e.g., high CBV relates to specific vessel locations with large VVF. Moreover, we find significant changes in CBV distribution and vasculature due to ageing (5 vs. 21 month-old mice), highlighting the sensitivity of our approach. Overall, we are able to associate CBV with vascular structure—and track its longitudinal changes—at the artery-vein, venules, arteriole, and capillary levels. We believe that this combined approach can be a powerful tool for studying other acute (e.g., brain injuries), progressive (e.g., neurodegeneration) or induced pathological changes.

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“…This is a particularly critical context in the SNP where PMP22 shows its maximum expression. However, the biological consequences of the micromutation generate a complex phenotype which, as we have shown, also manifests in the CNS [47,48]. In addition, its presence in other cell types, and at the nuclear level, augurs other unelucidated roles with more systemic characteristics in the expression of the TrJ phenotype.…”

Section: Introductionmentioning

confidence: 66%

“…Recently, we have reported the presence of PMP22 protein in the TrJ model at the hippocampal level. Consistently, an anxious behavior seems to involve the hippocampal domines as a component of the TrJ clinical phenotype [47].…”

Section: Introductionmentioning

confidence: 84%

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In Vivo Ultrafast Doppler Imaging Combined with Confocal Microscopy and Behavioral Approaches to Gain Insight into the Central Expression of Peripheral Neuropathy in Trembler-J Mice

Martínez Barreiro,

Vázquez Alberdi,

De León

et al. 2023

Biology

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The main human hereditary peripheral neuropathy (Charcot-Marie-Tooth, CMT), manifests in progressive sensory and motor deficits. Mutations in the compact myelin protein gene pmp22 cause more than 50% of all CMTs. CMT1E is a subtype of CMT1 myelinopathy carrying micro-mutations in pmp22. The Trembler-J mice have a spontaneous mutation in pmp22 identical to that present in CMT1E human patients. PMP22 is mainly (but not exclusively) expressed in Schwann cells. Some studies have found the presence of pmp22 together with some anomalies in the CNS of CMT patients. Recently, we identified the presence of higher hippocampal pmp22 expression and elevated levels of anxious behavior in TrJ/+ compared to those observed in wt. In the present paper, we delve deeper into the central expression of the neuropathy modeled in Trembler-J analyzing in vivo the cerebrovascular component by Ultrafast Doppler, exploring the vascular structure by scanning laser confocal microscopy, and analyzing the behavioral profile by anxiety and motor difficulty tests. We have found that TrJ/+ hippocampi have increased blood flow and a higher vessel volume compared with the wild type. Together with this, we found an anxiety-like profile in TrJ/+ and the motor difficulties described earlier. We demonstrate that there are specific cerebrovascular hemodynamics associated with a vascular structure and anxious behavior associated with the TrJ/+ clinical phenotype, a model of the human CMT1E disease.

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Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests

Cited by 10 publications

References 97 publications

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

Curcumin and Ethanol Effects in Trembler-J Schwann Cell Culture

Intensity distribution segmentation in ultrafast Doppler combined with scanning laser confocal microscopy for assessing vascular changes associated with ageing in murine hippocampi

In Vivo Ultrafast Doppler Imaging Combined with Confocal Microscopy and Behavioral Approaches to Gain Insight into the Central Expression of Peripheral Neuropathy in Trembler-J Mice

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