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Oxidative stress modulation in neurodegenerative diseases
No full textThe primary pathological feature of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis is the slow and progressive selective dysfunction and loss of neurons and axons in the central nervous system. Despite different triggering events, a common feature is the involvement of oxidative stress. Several evidences indicate that oxidative stress is critical for neurodegeneration. Here, we review the impact of oxidative stress involvement in neurodegenerative disorders, and discuss its contribution to neurons damage. We also discuss potential antioxidant therapies to modulate oxidative stress in this group of diseases. A better understanding of the imbalance between the production of reactive oxygen species and the ability of nervous system to remove them or repair the ensuing damage will be crucial for the development of new potential therapeutic strategies
Lithium therapy is able to reduce oxidative stress in amyotrophic lateral sclerosis patients
No full textObjectives: The causes of motorneurons loss in
Amyotrophic Lateral Sclerosis (ALS) are still unknown, but
accumulating evidences indicate that oxidative stress is
involved in the pathogenesis of this disease. Recently, a
possible role of lithium salts on ALS treatment has been
proposed. Lithium, a mood-stabilizing drug, is increasingly
recognized as neuroprotectant, mainly for mechanisms
linked to autophagy.
Methods: We tested, in an open label therapeutic trial, the
effect of lithium, at targeted plasma levels ranging from 0.4
to 0.8 mEq/liter, on clinical and oxidative stress-related
laboratory parameters in 30 ALS patients. In the enrolled
patients, we assessed blood levels of advanced oxidation
protein products (AOPP), ferric reducing ability of plasma
(FRAP), total glutathione, as well as disease-related
ALSFRS-r andMRC scales at baseline and at 6 months after
the targeted plasma lithium level was achieved.
Results: Reduction ofAOPP (p=0.005) and increase of total
glutathione (p=0.002), as compared to the values before
treatment, were observed. FRAP increased but not
significantly. Clinical evaluations at 6 months after the
targeted plasma lithium level was achieved, showed a
decrease of ALS-FRS and MRC scale scores compared to
pre-treatment’s one, but not significantly.
Conclusion: Lithium therapy is able to reduce circulating
levels of blood oxidative stress markers inALS.Whether or
not the modification of oxidative stress markers and antioxidant
defence is related to a direct effect of this drug on
pathogenic mechanism of the disease is still an open
question, to be addressed with long term studies
Effects of aerobic training on exercise-related oxidative stress in mitochondrial myopathies.
No full textIn mitochondrial myopathies with respiratory chain deficiency impairment of energy cell production may lead to in excess reactive oxygen species generation with consequent oxidative stress and cell damage. Aerobic training has been showed to increase muscle performance in patients with mitochondrial myopathies. Aim of this study has been to evaluate, in 7 patients (6 F e 1M, mean age 44.9 ± 12.1 years) affected by mitochondrial disease, concomitantly to lactate exercise curve, the occurrence of oxidative stress, as indicated by circulating levels of lipoperoxides, in rest condition and as effect of exercise, and also, to verify if an aerobic training program is able to modify, in these patients, ox-redox balance efficiency. At rest and before training blood level of lipoperoxides was 382.4 ± 37.8 AU, compared to controls (318.7 ± 63.8; P<0.05), this corresponding to a moderate oxidative stress degree according to the adopted scale. During incremental exercise blood level of lipoperoxides did not increase, but maintained significantly higher compared to controls. After an aerobic training of 10 weeks the blood level of lipoperoxides decreased by 13.7% at rest (P<0.01) and 10.4%, 8.6% and 8.5% respectively at the corresponding times during the exercise test (P=0.06). These data indicate that, in mitochondrial patients, oxidative stress occurs and that an aerobic training is useful in partially reverting this condition
Amyotrophic lateral sclerosis with long lasting disease course and SOD1 and TARDBP mutations: Report of two cases and overview of the literature.
No full textIntroduction
Despite its canonical nosographic definition as a
progressive neurodegenerative disorder typically
involving both lower and upper motor neurons,
leading to progressive muscle paralysis and death
approximately 2–4 years after symptom onset,
amyotrophic lateral sclerosis (ALS) is a heterogeneous
disease, including clinical presentation and
disease course. Forms with exclusive/predominant
upper or lower motor neuron involvement are
known, as well as subgroups of patients with a
long disease course. ALS is sporadic in approximately
90% of cases, whereas about 10% of cases
are familial (1). Mutations in the copper/zinc
superoxide dismutase (SOD1) gene were first
reported in familial ALS patients and account for
approximately 20% of these patients (2); subsequently,
a growing number of ALS-causing genes
have been identified, among which is the TARDBP
gene, coding for the TAR DNA-binding protein 43
(TDP-43) (3). In addition, several known familiar
ALS mutations have also been reported in apparently
sporadic ALS cases, underlying the complex
genetic heterogeneity of ALS pathology.
We describe here two cases of apparently sporadic
ALS associated with mutations, respectively, in
SOD1 and TARDP genes, characterized by predominant
lower motor neuron limb involvement and
long disease course.
Cases description
Case 1
A 70-years old Caucasian female came to our
attention for a 12-year history of slowly progressive,
mainly distal, hyposthenia and hypotrophy involving
the four limbs; at first symptoms involved the left
hand, mainly dorsal interosseous muscles, and
roughly three years later left arm muscles; then,
late in this interval, contralateral limb involvement,
first the lower, then the upper one, began to occur.
No family history of neuromuscular disorders was
reported. Neurological evaluation showed diffuse
and symmetric muscle weakness and hypotrophy at
the four limbs, osteo-tendon hyporeflexia and
indifferent cutaneous plantar reflex bilaterally;
no sensitive, bulbar or respiratory impairment
was documented, or bladder dysfunctions.
Electrophysiological examinations were consistent
with second motor neurons damage; however,
motor evoked potentials demonstrated subtle
abnormalities at upper motor neurons level, represented
by a prolongation of the central conduction
time at the four limbs. A subsequent extensive workout,
including laboratory examinations, brain and
spine MRI, cerebrospinal fluid analysis, was unremarkable.
Molecular DNA analysis, performed by
automatic sequencing, revealed a heterozygous
mutation in the SOD1 gene (A4G transition in
exon 5, position 365), this determining the aminoacid substitution p.E121G. DNA analysis searching
for mutations of the FUS, TARDBP and SMN1
genes was negative.
Case 2
A 55-years old Italian male, of Sardinian origin,
came to our attention for a 13-year history of slowly
progressive, symmetrical, mainly distal, hyposthenia
involving the four limbs, with cramps and fasciculations.
Neurological examination showed diffuse
distal hypotrophy and weakness, brisk osteo-tendon
reflexes at upper limbs, abolished osteo-tendon
reflexes at lower limbs, mild flexor plantar reflexes,
diffuse fasciculations; no sensitive, bulbar or respiratory
impairment was present, or bladder dysfunctions.
Electromyography was consistent with second
motor neurons damage. Motor evoked potentials
showed mild abnormal function of upper motor
neurons: in detail, at upper limbs, motor evoked
potentials were bilaterally reduced in amplitude,
whereas at lower limbs, motor evoked potentials
were reduced in amplitude, with a prolongation of
the central conduction time. Additionally, a psychiatric
history of bipolar disorder was present, without
evidences of cognitive impairment. No family history
of neuromuscular disorders was reported.
Laboratory examinations, brain and spine MRI,
and cerebrospinal fluid analysis, were unremarkable.
Molecular DNA analysis showed a heterozygous
c.1144G-4A mutation in the TARDBP gene (G-4A
transition at nucleotide 1144, exon 6), determining
the amino acid substitution p.A382T. Molecular
analysis of SOD1, FUS and SMN1 genes was
negative.
Discussion
Since its first reports and despite its monogenic
nature, the great clinical heterogeneity of genetic
ALS has been clear, also at the level of the same
mutation in the same gene, this raising the fundamental
question about the mechanisms underlying
the observed phenotypic variability. This is particularly
true when dealing with less common clinical
forms as is the case of those with very long disease
course.
We here first describe an apparently sporadic
case, disease onset at the age of 58 years, with
predominant lower motor neuron involvement and
slow disease course, carrying the p.E121G heterozygous
missense mutation of the SOD1 gene. This
mutation was first reported by Canosa et al. (4) in
an Italian male patient, with disease onset at the age
of 70 years and an apparently sporadic 14-year ALS
course mainly involving the lower motor neurons,
finally leading to dysarthria, dysphagia and respiratory
failure. Subsequently, this mutation was
reported by Dangoumau et al. (5) in a French
patient with a slowly progressive ALS phenotype
and disease onset at the age of 70 years; in addition,
these authors carried out functional studies in the
motor neuronal cell line NSC34 and in a primary
culture of mouse motor neurons, revealing that the
mutation p.E121G induced cytoplasm aggregates,
as well as reduced cell viability under oxidative
stress, thus supporting the hypothesis of a pathogenic
role of the mutation.
Also, the second patient, with a TARDBP
p.A382T missense mutation, presented a clinical
phenotype of long lasting disease course and predominant
lower motor neuron involvement,
although, as for the first case and due to the quite
long time-elapse between disease onset and time of
observation, we cannot exclude more subtle signs of
upper motor neuron involvement as is the case for
deep tendon hyperreflexia. It was previously
reported that ALS patients of Sardinian ancestry
have a higher frequency than expected of the
TARDBP p.A382T missense mutation (6,7).
Borghero et al. (8) reported in a cohort of 375
ALS patients of Sardinian origin a 25% occurrence
of this mutation in familial cases and 19.3% in
sporadic cases; regarding clinical phenotype,
patients with a TARDBP p.A382T heterozygous
mutation had the longest median survival up to
6.5 years and four patients showed extrapyramidal
signs. Additionally, Cannas et al. (9) showed that
the clinical presentation of the p.A382T TARDBP
mutation may include forms of Parkinsonism in
which the extrapyramidal signs are the crucial core
of the disease at onset. Therefore, the present report
seems to expand the clinical spectrum of the
TARDBP p.A382T heterozygous mutation, this
case being characterized by predominant lower
limb involvement. In both cases family history
resulted negative, although DNA analysis of other
family members was not possible.
Taken together, these case reports further underline
the clinical heterogeneity of ALS disease and the
need to investigate deep inside the pathophysiological
mechanisms of ALS pathology, in particular
to determine genetic and non-genetic factors modulating
ALS phenotype
Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.
No full textAmyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration
Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art.
No full textLack of association between the APEX1 Asp148Glu polymorphism and sporadic Amyotrophic Lateral Sclerosis
No full textImpairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the
apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be
associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1
Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression.
We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in
APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site
of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the
Italian population
Relation between cerebrospinal fluid oxidative stress biomarkers and intrathecal Ig synthesis in multiple sclerosis
No full textIntroduction: Oxidative stress has been implicated in disease progression and central nervous system (CNS) tissue damage in multiple sclerosis (MS) and may be related to CNS inflammation. The objective of the present study was to evaluate if cerebrospinal fluid (CSF) oxidative stress biomarkers (advanced oxidation protein products (AOPP) and
ferric reducing ability (FRA)) could be related to intrathecal IgG or IgM synthesis in MS patients. Material and methods: 54 consecutively admitted patients with clinically isolated syndrome (CIS) suggestive of MS or with MS were included. CSF samples collected at time of diagnosis were evaluated for physicochemical analysis, presence of oligoclonal
Ig bands, AOPP and FRA levels. Results: Oligoclonal intrathecal Ig bands were found in 100% of patients (2 subjects presented only 1 oligoclonal band). In 11 patients intrathecal IgM synthesis was detected. No relation was found between CSF AOPP levels or CSF FRA values and number of oligoclonal IgG bands (pvalues 0.3 and 0.6, respectively). No difference in CSF AOPP levels or CSF FRA values was observed between patients with intrathecal IgM synthesis and those without IgM synthesis. Conclusions: Our results seem to indicate that CSF oxidative stress
biomarkers are not related to intrathecal Ig synthesis
Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis
No full textImpairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population
Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues.
No full textCoenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology
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