The demonstration of the visual area by means of the atrophic degeneration method in the work of Bartolomeo Panizza (1855).
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History, 19th Century↗
Biomedical subjects
P Mazzarello
Publications and source records attributed to P Mazzarello.
Myoclonus epilepsy and ragged-red fibers: blood mitochondrial DNA heteroplasmy in affected and asymptomatic members of a family.
By a rapid PCR-based method to assess the 8344 mtDNA mutation associated with MERRF disease, we have studied DNA from blood samples of 10 individuals belonging to a family spanning four generations in which one patient showed the complete MERRF phenotype, three other members were less severely affected, while the remaining were unaffected. The percentage of mutant mtDNA was quantified by laser-densitometric scanning of the negative photographic sheets of the agarose gels. The results showed that the MERRF patient had 53% of mutated mtDNA while the two less affected patients had 62% and 14% of mutated mtDNA, respectively. However, a high percentage of mutated genomes (up to 64%) was also found in some unaffected relatives. These results show that although on one hand the mutation is probably the primary cause of the disease, on the other hand the relative amount of mutated mtDNA in blood samples is not indicative of its clinical expression.
Adolescent↗
Enzymes of DNA metabolism in a patient with the Wiedemann-Rautenstrauch progeroid syndrome.
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DNA Glycosylases↗
Uracil-DNA glycosylases preferentially excise mispaired uracil.
We have investigated the substrate specificity of human, viral and bacterial uracil-DNA glycosylases employing as substrate double-stranded oligonucleotides containing in the same position of the 5'-32P-labelled strand an uracil residue facing, on the complementary strand, guanine (mimicking cytosine deamination) or adenine (mimicking dUTP misincorporation). The enzyme removal of uracil was monitored and quantified by the generation of alkali-sensitive apyrimidinic sites. All three uracil-DNA glycosylases excise uracil from mispaired oligonucleotides (U/G) more efficiently than from paired oligonucleotides (U/A). The enzymes also remove uracil from single-stranded oligonucleotide with an efficiency similar to that observed with U/A paired oligonucleotide. The efficient recognition of U/G mispair by uracil-DNA glycosylase is important in minimizing miscoding transcripts and C/G-->T/A transitions in proliferating cells.
Animals↗
Uracil in OriS of herpes simplex 1 alters its specific recognition by origin binding protein (OBP): does virus induced uracil-DNA glycosylase play a key role in viral reactivation and replication?
We have recently demonstrated that mammalian uracil-DNA glycosylase activity is undetectable in adult neurons. On the basis of this finding we hypothesized that uracil, derived either from oxidative deamination of cytosine or misincorporation of dUMP in place of dTMP during DNA repair by the unique nuclear DNA polymerase present in adult neurons, DNA polymerase beta, might accumulate in neuronal DNA. Uracil residues could also arise in the herpes simplex 1 (HSV1) genome during latency in nerve cells. We therefore suggest a role for the virus encoded uracil-DNA glycosylase in HSV1 reactivation and in the first steps of DNA replication. We show here 1) that the viral DNA polymerase incorporates dUTP in place of dTTP with a comparable efficiency in vitro; 2) that virus specific DNA/protein interactions between the virus encoded origin binding protein and its target DNA sequence is altered by the presence of uracil residues in its central region TCGCA. Thus uracil, present in viral OriS or other key sequences could hamper the process leading to viral reactivation. Hence, HSV1 uracil-DNA glycosylase, dispensable in viral proliferation in tissue culture, could be essential in neurons for the "cleansing" of the viral genome of uracil residues before the start of replication.
Base Sequence↗
DNA repair mechanisms in neurological diseases: facts and hypotheses.
DNA repair mechanisms usually consist of a complex network of enzymatic reactions catalyzed by a large family of mutually interacting gene products. Thus deficiency, alteration or low levels of a single enzyme and/or of auxiliary proteins might impair a repair process. There are several indications suggesting that some enzymes involved both in DNA replication and repair are less abundant if not completely absent in stationary and non replicating cells. Postmitotic brain cell does not replicate its genome and has lower levels of several DNA repair enzymes. This could impair the DNA repair capacity and render the nervous system prone to the accumulation of DNA lesions. Some human diseases clearly characterized by a DNA repair deficiency, such as xeroderma pigmentosum, ataxia-telangiectasia and Cockayne syndrome, show neurodegeneration as one of the main clinical and pathological features. On the other hand there is evidence that some diseases characterized by primary neuronal degeneration (such as amyotrophic lateral sclerosis and Alzheimer disease) may have alterations in the DNA repair systems as well. DNA repair thus appears important to maintain the functional integrity of the nervous system and an accumulation of DNA damages in neurons as a result of impaired DNA repair mechanisms may lead to neuronal degenerations.
Animals↗
Thiamin mono- and pyrophosphatase activities from brain homogenate of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia patients.
Thiamin-pyrophosphatase (TPPase) and thiamin-monophosphatase (TMPase) were determined using a spectrophotometric method at various pH values (5.5, 7.5, and 9.0) in brain tissue obtained at autopsy from amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) patients from Guam and from Guamanian patients who died from other diseases (controls). TPPase separation by thin-layer polyacrylamide gel isoelectric focusing (IEF) was also performed using both gray and white matter. TPPase content, chemically determined at pH 9.0, was found to be significantly reduced in the frontal cortex of ALS and PD patients compared to controls. TMPase content, on the contrary, was unchanged. IEF analysis showed 9 clear-cut bands with TPPase activity in the pH range 5.4-7.2 and a broad band at pH 4.7-5.2. The enzymatic activity was higher in gray than in white matter. In one patient the pattern was clearly different, with two additional bands observed at pH 7.1 and 6.7, and thought to be due to genetic microheterogeneity.
Aged↗
Thiamin contents of cerebrospinal fluid, plasma and erythrocytes in cerebellar ataxias.
Free thiamin and thiamin monophosphate have been found in the cerebrospinal fluid, plasma and in erythrocytes of patients suffering from ataxia of different origins. In erythrocytes, thiamin pyrophosphate was also measured. In a limited number of cases, uptake of 14C-thiamin by erythrocytes was found as well. Controls were hospitalized patients affected by chronic neurological diseases without any clinical sign of thiamin deficiency. The results showed a significant decrease in thiamin and thiamin monophosphate in the cerebrospinal fluid and in the plasma of ataxic subjects, in comparison to controls. In erythrocytes, only thiamin pyrophosphate levels had decreased. The uptake of 14C-thiamin by erythrocytes was similar in both ataxic and control groups. These results were comparable to those observed in thiamin-deficient individuals, like alcoholic patients, and prompted further investigation into thiamin metabolism in these diseases.
Adult↗
The specific binding of nuclear protein(s) to the cAMP responsive element (CRE) sequence (TGACGTCA) is reduced by the misincorporation of U and increased by the deamination of C.
Point mutations in the cAMP-responsive element (CRE) of the rat somatostatin gene promoter/enhancer sequence (TGACGTCA) were used as a model for assessing the effect of uracil, deriving either from misincorporation during DNA synthesis (T----U) or cytosine deamination (C----U), on the binding of sequence/specific regulatory proteins. The results show that the T----U conversion in both strands of the CRE palindromic sequence reduces its affinity for the CRE binding factor(s), suggesting the crucial role of the methyl group contributed by T for the correct recognition of the sequence. On the other hand, deamination of C in the CpG central dinucleotide (CpG----UpG) causes an increase of binding affinity which is further enhanced by the contemporary deamination in both strands. Then, both uracil misincorporation and cytosine deamination alter the binding to CRE sequence in vitro, suggesting that uracil, if not removed by uracil DNA-glycosylase, could be dangerous for cellular functions.
Animals↗
Activity profiles of enzymes that control the uracil incorporation into DNA during neuronal development.
We have shown that DNA polymerase beta, the only nuclear DNA polymerase present in adult neurons, cannot discriminate between dTTP and dUTP, having the same Km for both substrates. This fact suggests that during reparative DNA synthesis, in adult neurons, dUMP residues can be incorporated into DNA. Since uracil DNA-glycosylase functions to prevent the mutagenic effects of uracil in DNA coming as a product of deamination of cytosine residues or as a result of dUMP incorporation by DNA polymerase, we have studied the perinatal activity of uracil DNA-glycosylase and of 2 enzymes (nucleoside diphosphokinase and dUTPase) involved in dUTP metabolism. Our data indicate that during neuronal development there is a rapid decrease in uracil DNA-glycosylase which could impair the removal of uracil present in DNA in adult neurons. However, misincorporation of dUMP into DNA might be kept to a low frequency by the action of dUTPase present at all developmental stages.
Animals↗
Misincorporation of uracil into DNA as possible contributor to neuronal aging and abiotrophy.
Neuronal aging and abiotrophy may be related to the abnormal presence of uracil in DNA. Evidence which could support this hypothesis exists: 1) DNA polymerase beta, the only nuclear DNA polymerase present in adult neurons which is able to repair damaged DNA, incorporates dUTP or dTTP with the same efficiency. This suggests that in adult neurons the incorporation of dUTP into DNA is solely dependent on the relative intracellular concentration of dUTP; 2) uracil into DNA also arises from cytosine deamination; 3) at birth, when neurons stop proliferating, uracil DNA-glycosylase, the enzyme responsible of the removal of uracil from DNA, nearly disappears; 4) a significant replacement of thymine by uracil in DNA could produce genetic instability which in turn could affect the recognition of DNA sequences by enzymes and/or by regulatory DNA binding proteins. Thus enzymatic defects which might alter the intracellular dUTP pool, in different neuronal systems, could account for the multiplicity of the clinical manifestations of aging and neurodegenerative disorders. The increase of the age-specific rate of abiotrophic diseases may be due to accumulation with time of uracil containing DNA.
Cell Survival↗
Thiamine, thiamine phosphates and thiamine metabolizing enzymes in synaptosomes of rat brain.
Thiamine and thiamine mono-, pyro- and triphosphate were found at detectable levels in synaptosomes isolated from whole rat brain. Synaptosomes prepared from whole brain, cerebellum and medulla were also found to contain uridine and inosine mono- and diphosphatases as well as the thiamine pyrophosphate synthetizing and hydrolyzing enzymes, but no thiamine monophosphatase. By isoelectric focusing on thin layer polyacrylamide gel of Triton X-100 homogenates of synaptosomes, thiamine pyrophosphatase activity could be separated into 10 bands with different isoelectric points. The contents of thiamine compounds and enzymes in synaptosomes were generally lower than those found in neuronal cell bodies.
Animals↗
Different distribution of thiaminpyrophosphatase activity in neuronal and glial cell enriched fractions from human and rat brain: an isoelectric focusing investigation.
Enriched fractions of neuronal and glial cells from rat and human (autoptical specimens of frontal cortex) brains were assayed for thiaminpyrophosphatase (TPPase) activity by isoelectric focusing (IEF). Glial and neuronal fractions yielded about 0.16 and 0.03 g/g of wet tissue respectively. Purity was estimated to be 85-90%. The isolated fractions were homogenized in the presence of 1% Triton X-100, and IEF was carried out on thin layer polyacrylamide gel in a pH range of 3.5-9.5, using Ampholine PAG plates. TPPase activity of the protein bands was assayed by laser-densitometry, after incubation with thiaminpyrophosphate in an appropriate buffer and PbS staining. IEF analysis showed that TPPase activity was present almost exclusively in the neuronal fraction (at levels 16-fold higher than those found in the glial fraction). After IEF, TPPase activity was present in 10 distinct protein bands with different isoelectric points. These preliminary data suggest that TPPase may be involved in the neuronal activity of rat and human brain.
Aged↗
Transient intrathecal IgG synthesis in herpes zoster myelitis: 2 case reports.
Alterations in cerebrospinal fluid in 2 cases of viral myelopathy associated with herpes zoster infection are reported. Viral myelopathy is a rare complication of herpes zoster. Quantitatively there was a slight increase in IgG production and oligoclonal IgG bands were detected by isoelectric focusing. These parameters returned to normal after 1 year suggesting a transient involvement of the central nervous system.
Adult↗
A lead conversion method for staining thiamine pyrophosphatase and other phosphatases in rat brain after thin layer polyacrylamide gel isoelectric focusing.
Rat brain thiamine pyrophosphatase (TPPase) was separated by thin layer polyacrylamide gel isoelectric focusing (IF) and stained with a modification of the lead conversion method of Allen and Hyncik (1963). 10 bands with TPPase activity were observed in the pH range 4.6-7.1. The overall IF pattern of TPPase was similar to that of uridine diphosphatase and inosine diphosphatase but was clearly different from that of adenosine diphosphatase, p-nitrophenyl phosphatase, alpha-naphthyl phosphatase and thiamine monophosphatase. A semiquantitative assessment of TPPase isoenzymes has been performed using laser densitometry.
Animals↗
Cerebrospinal fluid IgG changes in neurosyphilis after high-dose penicillin G treatment.
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Humans↗
Inversion of T/TMP ratio in ALS: a specific finding?
Thiamine (T) and thiamine monophosphate (TMP) levels were determined by an electrophoretic fluorometric method in the CSF of patients with typical sporadic ALS (50 cases), in other motor neuron diseases (MND) (14 cases) and in patients with upper and/or lower motor neuron lesions of varying origin (disseminated sclerosis, polyneuropathy, spondylotic myelopathy). T/TMP ratio was greater than or equal to 1 in a high percentage of patients with typical sporadic ALS (94%), in 35.7% of cases with other MND, while it was below 1 in the all other patients. The decrease of TMP with the inversion of the T/TMP ratio is a finding highly specific to typical sporadic ALS.
Adult↗
Is progressive multifocal leukoencephalopathy associated with intrathecal IgG synthesis?
Examination of the cerebrospinal fluid by isoelectric focusing was done in 2 cases of progressive multifocal leukoencephalopathy (PML). The diagnosis was confirmed at autopsy in one case. IgG oligoclonal bands were found in both, suggesting that there was intrathecal immunoglobulin synthesis. Production may be due to a specific intrathecal response to papova virus or to IgG oligoclonal formation by lymphoma cells confined to the central nervous system or to a specific immune response to tumor cell antigens.
Aged↗