Methods for computing the standard errors of branching points in an evolutionary tree and their application to molecular data from humans and apes

Statistical methods for computing the standard errors of the branching points of an evolutionary tree are developed. These methods are for the unweighted pair-group method-determined (UPGMA) trees reconstructed from molecular data such as amino acid sequences, nucleotide sequences, restriction-sites data, and electrophoretic distances. They were applied to data for the human, chimpanzee, gorilla, orangutan, and gibbon species. Among the four different sets of data used, DNA sequences for an 895-nucleotide segment of mitochondrial DNA (Brown et al. 1982) gave the most reliable tree, whereas electrophoretic data (Bruce and Ayala 1979) gave the least reliable one. The DNA sequence data suggested that the chimpanzee is the closest and that the gorilla is the next closest to the human species. The orangutan and gibbon are more distantly related to man than is the gorilla. This topology of the tree is in agreement with that for the tree obtained from chromosomal studies and DNA-hybridization experiments. However, the difference between the branching point for the human and the chimpanzee species and that for the gorilla species and the human-chimpanzee group is not statistically significant. In addition to this analysis, various factors that affect the accuracy of an estimated tree are discussed.      

The 12th J. A. F. Stevenson memorial lecture. Aging, Alzheimer's disease, and the cholinergic system

Aging does not affect tissues in a uniform fashion. Within the brain, substantial neuronal dropout occurs with age in the cholinergic medial basal forebrain complex, the noradrenergic locus coeruleus, and the dopaminergic substantia nigra pars compacta. These areas are also struck by diseases that are sharply age dependent. Alzheimer's disease causes neuronal destruction in the cholinergic cells of the medial basal forebrain and noradrenergic cells of the locus coeruleus. Parkinson's disease causes neuronal destruction mainly in the substantia nigra but with some destruction in the locus coeruleus. Parkinsonism-dementia affects all three areas. Alzheimer's disease is responsible for 50-60% of all cases of dementia. Severe dementia rises in frequency from less than 1% of the population at age 65-70 to over 15% by age 85. The cause of the disease is unknown. No method of prevention is known and present treatments are ineffective, although modest improvement has been reported for various therapeutic regimens designed to stimulate the cholinergic system. The neuronal systems identified as being affected in Alzheimer's disease and in the dementia of Parkinsonism correspond with those shown many years ago to be associated with the reticular activating system. This correspondence permits a new hypothesis of cognition and memory to be put forward, as well as a reinterpretation of data from animal research on the reticular activating system performed over a quarter of a century ago. The locus coeruleus is proposed as the noradrenergic element sensitizing the cortex to conscious recognition of real time events. The medial basal forebrain complex is proposed as the system registering the conscious event for storage and as the readout device when it is subsequently redisplayed in the cortex as memory. Storage could either be in the temporal lobe, in several areas of cortex with feedback to the medial basal forebrain, or in the cholinergic cells themselves.     

Changes in Muscarinic Binding in Distant Brain Regions Showing Neuronal Losses After Folic Acid Injections into the Substantia Innominata

Injection of folic acid (FA) into the nucleus substantia innominata (NSI) was found to decrease [3H]quinuclidinyl benzilate ([3H]QNB) binding in the frontal cortex, pyriform cortex, amygdala, and the NSI itself without changing the KD. Binding in the thalamus, caudate nucleus, hippocampus, and substantia nigra was not affected. [3H]Flunitrazepam binding was unchanged in all eight regions studied. Previous work indicates FA injections into the NSI produce epileptiform activity and cause loss of GABAergic and possibly other neurons in the frontal and pyriform cortices, the amygdala, and thalamus. The reductions of [3H]QNB binding in the first three of these regions are interpreted as indicating that many of the neurons lost are cholinoceptive, a finding that supports the previous hypothesis that activation of cholinergic projections from the NSI is an important part of the mechanism of cell loss in these regions.     

Some factors influencing the neurotoxicity of intrastriatal injections of kainic acid

Intrastriatal injections of kainic acid are known to destroy striatal neurons including many containing choline acetyltransferase (CAT) and glutamic acid decarboxylase (GAD). Using these enzymes as indices of neuronal loss, the neurotoxicity of small doses of kainic acid was found to be influenced by injection time and volume. It was partly blocked by coninjection of some but not all glutamate antagonists or by prior lesioning of the corticostriatal tract. Other adjuvants, drugs, or lesions tested had little modifying effect, except that changes in the dopaminergic system seemed to increase the toxicity towards cholinergic but not GABAnergic systems. High-affinity glutamate accumulation by neostriatal synaptosomes was significantly increased 1–7 days following kainic acid injections. MAO and acetylcholinesterase activities were depressed in kainic acid-lesioned striata but not nearly as much as were CAT and GAD. An indirect mechanism involving glutamate release and inhibition of reuptake is suggested for kainic acid neurotoxicity.     

ENZYMES ASSOCIATED WITH THE METABOLISM OF CATECHOLAMINES, ACETYLCHOLINE AND GABA IN HUMAN CONTROLS AND PATIENTS WITH PARKINSON''S DISEASE AND HUNTINGTON''S CHOREA

—Tyrosine hydroxylase (TH), dopa decarboxylase (DDC), glutamic acid decarboxylase (GAD), choline acetyltransferase (CAT), and acetylcholinesterase (AChE) were measured in 18–55 areas of brain from humans post mortem. Individuals meeting sudden and unexpected death (22), patients dying in hospital with non–neurological illness (6), Parkinson's disease (12), Huntington's chorea (8), terminal coma (6) or head injury (2) were included in the series. The absolute values obtained compared favourably with some previous human studies where high values for these enzymes were obtained, as well as with monkey and baboon data. The regional distributions of the enzymes were also comparable to those previously reported in human and animal studies. A number of important points with regard to human tissue seemed to emerge from the study. The mode of death was not a factor in enzyme levels in non–neurological and non-coma cases. Post mortem delay did not seem to be a major factor either even though a substantial decline in GAD, TH and DDC could be demonstrated in rats left several hours between sacrifice and removal of the brain for assay. Age had a highly significant effect in certain areas of brain. The decline typically followed a curvilinear pattern (activity = A/age + B with the sharpest drops being in the younger age groups). DDC seemed to be the enzyme most severely affected by age but all the enzymes showed declines in certain brain areas, while in other areas there was no significant decline. All the enzymes were very depressed by coma from illness except AChE. TH and DDC in the brain stem were, however, not affected in the head injury cases. The Parkinsonian cases showed a sharply decreased TH activity in the substantia nigra, caudate and putamen. There were decreases in GAD in the globus pallidus (GP) and substantia nigra with marginal decreases in the neostriatum. CAT levels in the extrapyramidal nuclei were normal. In Huntington's chorea there was a substantial decrease in GAD in all the extrapyramidal structures. There was a patchy loss of CAT in the neostriatum and locus coeruleus.     

CHEMICAL SPECIFICITY OF DOPAMINE TRANSPORT IN THE NIGRO-NEOSTRIATAL PROJECTION

Axoplasmic transport of dopamine in the nigro-neostriatal system has previously been shown by the specific accumulation of labelled dopamine in the striatum following injections of labelled DOPA or dopamine into the substantia nigra. To test the specificity, 17 different labelled materials (pipecolic acid, inulin, taurine, GABA, glycine, histidine, histamine, serotonin, 5-HTP, D-amphetamine, 3-methoxytyramine, dopamine, tyramine, norepinephrine, octopamine and high and low specificity activity DOPA) were injected into the substantia nigra and the distribution of radioactivity in the brain studied after 6 and 24 h. Only the catecholamines and octopamine gave evidence of specific accumulation in the ipsilateral striatum although some of the other compounds caused diffuse labelling of the striatum along with other brain areas.     

Ant genomics sheds light on the molecular regulation of social organization

Ants are powerful model systems for the study of cooperation and sociality. In this review, we discuss how recent advances in ant genomics have contributed to our understanding of the evolution and organization of insect societies at the molecular level.     

Lrrk2 interaction with α-synuclein in diffuse Lewy body disease

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of genetically inherited Parkinson’s disease (PD) and its more severe variant diffuse Lewy body disease (DLB). Pathological mutations in Lrrk2 are autosomal dominant, suggesting a gain of function. Mutations in α-synuclein also produce autosomal dominant disease. Here we report an interaction between Lrrk2 and α-synuclein in a series of diffuse Lewy body (DLB) cases and in an oxidative stress cell based assay. All five cases of DLB, but none of five controls, showed co-immunoprecipitation of Lrrk2 and α-synuclein in soluble brain extracts. Colocalization was also found in pathological deposits in DLB postmortem brains by double immunostaining. In HEK cells transfected simultaneously with plasmids expressing Lrrk2 and α-synuclein, co-immunoprecipitation of Lrrk2 and α-synuclein was detected when they were exposed to oxidative stress by H₂O₂. Taken together, these results suggest the possibility that in PD and related synucleinopathies, oxidative stress upregulates α-syn and Lrrk2 expression, paving the way for pathological interactions. New therapeutic approaches to PD and the synucleinopathies may result from limiting the interaction between Lrrk2 and α-synuclein.