Monogenic primary hypercholesterolaemia in South Africa

Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-1OO (FDB) are the two major causes of monogenic primary hypercholesterolaemia. In this review, FH and FDB are defined in relation to normal lipoprotein metabolism. In South Africa FH affects about 1% of Afrikaners, Jews and Indians, while FDB is probably a much rarer disorder. In Afrikaners, three 'founder' mutations are responsible for more than 80% of FH. The population genetics that created the exceptionally high frequency of FH and comparatively low frequency of FDB in various South African populations are described. The genetic organisation and itinerary of the normal low-density lipoprotein (LDL) receptor are reviewed, with particular emphasis on the structure- function relationships in the LDL receptor that have been clarified by the mutations found in South Africa. Finally, the clinical relevance of research into FH in South Africa is discussed

Myc inhibition impairs autophagosome formation

Autophagy, a major clearance route for most long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus presents as an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of JNK1 and Bcl2 phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder

Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts?

The largest group of currently known trinucleotide repeat diseases is caused by (CAG)n repeat expansions. These (CAG)n repeats are translated into polyglutamine tracts from both mutant and wild type alleles. Genetic and transgenic mouse data suggest that the expanded polyglutamines cause disease by conferring a novel deleterious gain of function on the mutant protein. These mutations are associated with the formation of intracellular inclusions. This review will consider findings from necropsy studies of human patients and transgenic mouse models of these diseases, along with in vitro models, in order to try to synthesise the current understanding of these diseases and the evidence for and against inclusion formation as a primary mechanism leading to pathology

Lysosomal storage diseases as disorders of autophagy

The cellular turnover of proteins and organelles requires cooperation between the autophagic and the lysosomal degradation pathways. A crucial step in this process is the fusion of the autophagosome with the lysosome. In our study we demonstrate that in Lysosomal Storage Disorders (LSDs) accumulation of undegraded substrates in lysosomes, due to deficiency of specific lysosomal enzymes, impairs the fusion between autophagosomes and lysosomes. This, in turn, leads to a progressive accumulation of poly-ubiquitinated protein aggregates and of dysfunctional mitochondria. These findings suggest that neurodegeneration in LSDs may share some mechanisms with late-onset neurodegenerative disorders in which the accumulation of protein aggregates is a prominent feature