E. Chiricozzi

E. Di Biase

G. Lunghi

M. Audano

M. Fazzari

N. Mitro

S. Sonnino

English

AIR Universita degli studi di Milano

MTU04-16
The oligosaccharide portion of ganglioside GM1 as
mitochondrial regulator
M. Fazzari1, G. Lunghi1, E. D. Biase1, M. Audano2, N. Mitro2, S.
Sonnino1, E. Chiricozzi1
1University of Milano, Department of Medical Biotechnology and
Translational Medicine, Segrate, Italy
2University of Milano, Department of Pharmacological and
Biomolecular Sciences, Milano, Italy
Functional data and clinical studies suggest the existence of a
positive loop between the age-dependent GM1 deficiency and alpha-
synuclein (aS) accumulation determining the neurodegeneration
onset of sporadic Parkinson’s Disease (PD). This loop is triggered
by the plasma membrane GM1 deficiency, which leads to a failure
of trophic signaling and to the aS accumulation, increasing the
susceptibility to neuronal death. Recently we shed new light on the
molecular basis underlying GM1 effects highlighting that GM1
oligosaccharide (OligoGM1) directly binds TrkA receptor, trigger-
ing TrkA-MAPK pathway activation which leads to neuronal
differentiation and protection. Following its administration to
B4galnt1+/ PD mouse model, OligoGM1 was found to completely
rescue the physical symptoms, reduce aS aggregates and restore
tyrosine-hydroxylase neurons. Since the mitochondrial dysfunction
plays a central role in the exacerbation of nigrostriatal degeneration
in PD, we decide to evaluate the putative OligoGM1 mitochondrial
modulation in murine neuroblastoma cells, N2a. Following its
exogenous administration, proteomic analysis revealed an increased
expression of proteins involved in mitochondrial bioenergetics and
in oxidative stress protection. By biochemical studies we found that
OligoGM1 protects N2a cells from MPTP toxic effect as well as
from mitochondrial oxidative stress. Moreover, by immunoblotting
we identified an increased expression of TOM20/HtrA2 mitochon-
drial proteins, whose reduced expression has been associated with
PD. At functional level, we found increased basal and uncoupled
mitochondrial respiration following OligoGM1 administration.
Collectively our data indicate a possible role of OligoGM1 as
mitochondrial regulator that by inducing mitochondriogenesis and
enhancing mitochondrial activity could determine mitochondrial
restoration in PD neurons.
MTU04-17
Reductive reprogramming: a not-so-radical hypothesis of
neurodegeneration
T. Foley
University of Scranton, Chemistry, Scranton, USA
Free radical-mediated oxidative stress, neuroinflammation, and
excitotoxicity have long been hypothesized to contribute to the
progression of Alzheimer’s disease and other aging-related neu-
rodegenerative disorders (NDD). Among these phenomena, the
significance of oxidative stress and, more generally, redox pertur-
bations, for NDD remain ill-defined and unsubstantiated. Here, I
argue that (i) free radical-mediated oxidations of biomolecules can
be dissociated from the progression of NDD, (ii) oxidative stress
fails as a descriptor of cellular redox states under conditions relevant
to disease, and (iii) aberrant upregulation of compensatory reducing
activities in neural cells, resulting in reductive shifts in thiol-based
redox potentials, may be an overlooked and paradoxical contributor
to disease progression. In particular, I summarize evidence, from
in vitro studies, which supports the view that reductive shifts in the
extracellular space can occur in response to oxidant and inflamma-
tory signals and that these have the potential to reduce putative
regulatory disulfide bonds in exofacial domains of the N-methyl-D-
aspartate (NMDA)-subtype of glutamate-gated receptors as well as
other synaptic regulatory proteins, leading potentially to aberrant
increases in neuronal excitability and, if sustained, excitotoxicity.
Moreover, I provide data from my laboratory which establishes the
presence in the brain, in vivo, of disulfide bonds in the NMDA
receptor as well as other glutamate and non-glutamate-gated
receptors. All of these are potential targets of reductive stress. This
novel reductive reprogramming hypothesis of neurodegeneration
provides an alternative view of redox perturbations in NDD and
links these to both neuroinflammation and excitotoxicity.
MTU04-18
The role of monocarboxylate transporter-1 on cognitive
deficits development during NAFLD
A. Hadjichambi1, P. Hosford2, L. Pellerin1
1UNIL, Department of Physiology, Lausanne, Switzerland
2UCL, Neuroscience, physiology and pharmacology, London, UK
Non-alcoholic fatty liver disease (NAFLD) is a major compli-
cation of obesity. Certain observations regarding NAFLD induced
neuropsychiatric alterations have been reported but mechanisms are
unknown. Monocarboxylate transporter-1 (MCT1) haploinsufficient
mice, which resist high fat diet (HFD) induced hepatic steatosis
represent an interesting model. Using a mouse model of NAFLD
(HFD+high fructose/glucose in water [HF/HG]) we investigated the
development of cognitive deficits and state of cerebral oxygenation
and cerebrovascular reactivity.
Behavioural tests (open field/novel object recognition/forced
swimming test [FST]) were performed in mice fed control diet (NC;
WT/MCT1 + /- +NC) or HFD HF/HG (WT/MCT1 + /- +HFD HF/
HG) for 16 weeks. Baseline cortical PO2 and in response to
systemic hypercapnia (10% CO2) was monitored under anaesthesia
by a fluorescence method. Microelectrode biosensors were used for
lactate measurements by cortical slices. EchoMRI was performed to
assess lean/fat mass.
Increased fat mass was observed in WT and MCT1 + /- mice on
HFD HF/HG compared to NC controls. Liver mass was only
significantly higher in WT+HFD HF/HG mice compared to controls.
Behavioural tests revealed no significant differences between groups
except for FST, which indicated a depression-related behaviour in
the WT+HFD HF/HG group compared to controls. This was not
observed with MCT1 + /-+HFD HF/HG mice. WT+HFD HF/HG
mice had a lower cerebral PO2 baseline and hypercapnia-induced
PO2 response compared to controls, while MCT1 + /- groups
remained unchanged. Tonic lactate release was unaltered between
all groups although the MCT1 + /-+HFD HF/HG group indicated a
decreased lactate tone trend.
Our results suggest that NAFLD is associated with a depression-
related behaviour and decreased cerebral PO2 baseline. MCT1
haploinsufficient mice were resistant to the reported phenotypes,
suggesting a link between liver metabolism and neuropathophysi-
ological alterations.
96 Journal of Neurochemistry © 2019 International Society for Neurochemistry, J. Neurochem. (2019) 150 (Suppl. 1), 73--161
© 2019 The Authors
MTU04 Molecular basis of disease (Session A)


The oligosaccharide portion of ganglioside GM1 as mitochondrial regulator

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The oligosaccharide portion of ganglioside GM1 as mitochondrial regulator

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