Genotype-Property Patient-Phenotype Relations Suggest that Proteome Exhaustion Can Cause Amyotrophic Lateral Sclerosis

Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability < 3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R2 = 0.51, p = 1.8 x 10-5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e.g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons

Pathogenesis of amyotrophic lateral sclerosis

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition. SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown. There are a wide range of potential mechanisms related to neurodegeneration. An increasing number of genetic factors are recognized. AREAS OF CONTROVERSY: There remains controversy, or lack of knowledge, in explaining how cellular events manifest as the complex human disease. There is controversy as to how well cellular and animal models of disease relate to the human disease. GROWING POINTS: Large-scale international collaborative genetic epidemiological studies are replacing local studies. Therapies related to pathogenesis remain elusive, with the greatest advances to date relating to provision of care (including multidisciplinary management) and supportive care (nutrition and respiratory support). AREAS TIMELY FOR DEVELOPING RESEARCH: The identification of C9orf72 hexanucleotide repeats as the most frequent genetic background to ALS, and the association with frontotemporal dementia, gives the potential of a genetic background against which to study other risk factors, triggers and pathogenic mechanisms, and to develop potential therapies

New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis

A number of genes have been linked to familial forms of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Over 150 mutations within the gene encoding superoxide dismutase 1 (SOD1) have been implicated in ALS, but why such mutations lead to ALS-associated cellular dysfunction is unclear. In this study, we identify how ALS-linked SOD1 mutations lead to changes in the cellular health of the yeast Saccharomyces cerevisiae We find that it is not the accumulation of aggregates but the loss of Sod1 protein stability that drives cellular dysfunction. The toxic effect of Sod1 instability does not correlate with a loss of mitochondrial function or increased production of reactive oxygen species, but instead prevents acidification of the vacuole, perturbs metabolic regulation and promotes senescence. Central to the toxic gain-of-function seen with the SOD1 mutants examined was an inability to regulate amino acid biosynthesis. We also report that leucine supplementation results in an improvement in motor function in a Caenorhabditis elegans model of ALS. Our data suggest that metabolic dysfunction plays an important role in Sod1-mediated toxicity in both the yeast and worm models of ALS

Does Glyphosate Acting as a Glycine Analogue Contribute To ALS?

 Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease involving several protein mutations in glycine-rich regions with limited treatment options. 90 - 95% of all cases are non-familial with epidemiological studies showing a significant increased risk in glyphosate-exposed workers. In this paper, we propose that glyphosate, the active ingredient in Roundup®, plays a role in ALS, mainly through mistakenly substituting for glycine during protein synthesis, disruption of mineral homeostasis as well as setting up a state of dysbiosis. Mouse models of ALS reveal a pre-symptomatic profile of gut dysbiosis. This dysbiotic state initiate a cascade of events initially impairing metabolism in the gut, and, ultimately, through a series of intermediate stages, leading to motor neuron axonal damage seen in ALS. Lipopolysaccharide, a toxic by-product of dysbiosis which contributes to the pathology, is shown to be statistically higher in ALS patients. In this paper we paint a compelling view of how glyphosate exerts its deleterious effects, including mitochondrial stress and oxidative damage through glycine substitution. Furthermore, its mineral chelation properties disrupt manganese, copper and zinc balance, and it induces glutamate toxicity in the synapse, which results in a die-back phenomenon in axons of motor neurons supplying the damaged skeletal muscles

Genetics of steer daily and residual feed intake in two tropical beef genotypes, and relationships among intake, body composition, growth and other post-weaning measures

Genetic parameters for Brahman (BRAH) and Tropical Composite (TCOMP) cattle were estimated for steer production traits recorded at weaning (WEAN), 80 days post-weaning (POSTW), feedlot entry (ENTRY) and after ∼120 days feedlot finishing (EXIT). The TCOMP was 50% Bos indicus, African Sanga or other tropically adapted Bos taurus, and 50% non-tropically adapted Bos taurus. Data involved 2216 steers, comprising 1007 BRAH by 53 sires and 1209 TCOMP by 50 sires. Individual daily feed intake (DFI) and residual feed intake (RFI) were assessed on 680 BRAH and 783 TCOMP steers over an ~70-day feedlot test. Other traits were liveweight (LWT), average daily gain (ADG), ultrasonically scanned rump (SP8) fat depth, rib (SRIB) fat depth, M. longissimus area (SEMA) and intra-muscular fat % (SIMF), body condition score (CS), hip height (HH), flight time (FT) and serum insulin-like growth factor-I concentration (IGF-I).BRAH were significantly (P < 0.05) lighter at ENTRY and EXIT, and had lower DFI (10.8 v. 13.2 kg/day) and RFI (–0.30 v. 0.17 kg/day), greater SP8 (5.8 v. 5.1 mm) but similar SRIB at ENTRY, lower SRIB (8.2 v. 8.9 mm) but similar SP8 at EXIT, and greater HH than TCOMP. Heritabilities for DFI, RFI, LWT, ADG, scanned body composition, HH and IGF-I measures, across measurement times, were generally in the 20 to 60% range for both genotypes. Genetic variance for RFI was 0.19 (kg/day)2 in BRAH and 0.41 (kg/day)2 in TCOMP, suggesting a clear potential to genetically change RFI in both genotypes. Trait variances and genetic correlations often differed between the genotypes, supporting the use of genotype-specific parameters in genetic evaluation. The genotype differences may be associated with evolutionary changes that have occurred in B. indicus as a part of their adaptation to tropical environments.Measures with potential to be used as genetic indicators of DFI were LWT measures in BRAH and TCOMP, ADG at ENTRY in TCOMP, and SP8 and SIMF at ENTRY in BRAH. Measures with potential to be genetic indicators of RFI were HH and ADG at ENTRY in BRAH, and IGF-I in both genotypes. Taller and faster-growing BRAH steers at ENTRY had genetically lower RFI. IGF-I was negatively genetically correlated with RFI whether IGF-I was measured at POSTW, ENTRY or EXIT. SRIB fatness at EXIT was strongly positively genetically correlated with RFI in TCOMP but only lowly correlated in BRAH. Fatness at ENTRY was lowly and negatively genetically correlated with RFI. The results emphasise the need for a population-specific understanding of trait relationships and of trait differences between measurement times if genetic indicator traits are to be utilised in genetic evaluation of RFI

A pathway branching in transcription initiation in Escherichia coli

In transcription initiation, all RNA polymerase molecules bound to a promoter have been conventionally supposed to proceed into elongation of transcript. However, for Escherichia coli RNA polymerase, evidence has been accumulated for a view that only its fraction can proceed into elongation and the rest is retained at a promoter in non-productive form: a pathway branching in transcription initiation. Proteins such as GreA and GreB affect these fractions at several promoters in vitro. To reveal the ubiquitous existence of the branched mechanism in E. coli, we searched for candidate genes whose transcription decreased by disruption of greA and greB using a DNA array. Among the arbitrarily selected 11 genes from over 100, the atpC, cspA and rpsA passed the test by Northern blotting. The Gre factors activated transcription initiation from their promoters in vitro, and the results demonstrated that the branched mechanism is exploited in vivo regulation. Consistently, decrease in the level of the GreA in an anaerobic stationary condition accompanied a decrease in the levels of transcripts of these genes