Molecular Pathogenesis of Huntington's Disease Flashcards
How is HD characterised pathologically?
- HD is characterised pathologically by selective degeneration of neurons in caudate and putamen, with less severe atrophy in the cerebral cortex.
- Cell loss in the striatum is not uniform and medium spiny neurons show particular sensitivity.
- It is not clear why cell death is confined to particular neuronal subtypes, since the gene is widely expressed throughout the brain and body.
Describe cell loss in the striatum in HD.
Cell loss in the striatum is not uniform and medium spiny neurons show particular sensitivity.
Why is cell death in HD confined to particular neuronal subtypes?
It is not clear why cell death is confined to particular neuronal subtypes, since the gene is widely expressed throughout the brain and body.
What is the sequence of pathogenic events in HD?
The sequence of pathogenic events in HD is still unclear. The function of the wild-type huntingtin (HTT) protein is not fully understood. A common feature of HD however is the accumulation of mutant protein in insoluble aggregates.
NIIs are a characteristic feature of HD. What are they?
NIIs are Neuronal Intranuclear Inclusions.
They contain huntingtin and ubiquitin.
NIIs are formed from the aggregation of abnormal polyglutamine expansions in neuronal nuclei.
NIIs appear more abundant in the brains of juvenile onset HD cases with large CAG repeat expansions.
However, these NIIs do not appear to be the cause of disease themselves: in mouse models and human brains, the location of the inclusions did not always correlate with cell toxicity.
Mutant HTT forms abnormal protein conformations e.g. b-sheet.
Describe the mutant HTT protein confirmation.
Mutant HTT forms abnormal protein confirmations such as beta sheets.
Mutant HTT is truncated by caspase 6 cleavage, producing toxic N-terminal fragments.
Processing of abnormal proteins (e.g. ubiquitin pathay) is altered in HD.
The toxicity of HTT is affected by post-translational modification and nuclear localisation.
What caspase is mutant HTT truncated by?
Mutant HTT is truncated by caspase 6 cleavage, producing toxic N-terminal fragments.
What affects the toxicity of HTT?
The toxicity of HTT is affected by post-translational modification and nuclear localisation.
Outline the intracellular molecular pathogenesis of HD postulated by Ross and Tabrizi in 2011.
1) . Mutant HTT undergoes a transformational change and interferes with cellular trafficking, especially the trafficking of Brain Derived Neurotrophic Factor (BDNF).
2) . Mutant HTT is cleaved at several points to generate toxic fragments with abnormal compact beta conformation. These abnormal proteins aggregate and form fibrillar structures.
3) . Pathogenic inclusion bodies are found in the nucleus, however, these are not the primary pathogenic species.
4) . A major action of mutant HTT is interference in gene transcription via PGC1a leading to decreased transcription of BDNF and nuclear encoded mitochondrial proteins.
5) . The effects on metabolism of mutant HTT could range from the cell dealing with abnormal protein, to direct and indirect effects on the mitochondria. These could impair energy metabolism and induce oxidative damage to the cell.
6) . Mutant HTT causes decreased transport and release of BDNF. The increased stimulation of extra-synaptic glutamate receptors takes place (e.g. in the NMDA receptors). This reduces the uptake of glutamate and leads to exotoxicity and increased susceptibility to metabolic toxic effects. Activating microglia produces increased inflammatory activity.
Therapeutic strategies may target some of these steps in the pathogenic chain of events.
What cellular process does mutant HTT particular interfere with?
Mutant HTT undergoes a transformational change and interferes with cellular trafficking, especially the trafficking of Brain Derived Neurotrophic Factor (BDNF).
What process involving mutant HTT leads to the formation of fibrillar structures?
Mutant HTT is cleaved at several points to generate toxic fragments with abnormal compact beta conformation. These abnormal proteins aggregate and form fibrillar structures.
True or False - pathogenic inclusion bodies found in the nucleus are the main pathogenic species.
Pathogenic inclusion bodies are found in the nucleus, however, these are not the primary pathogenic species.
How does mutant HTT interfere in gene transcription?
A major action of mutant HTT is interference in gene transcription via PGC1a leading to decreased transcription of BDNF and nuclear encoded mitochondrial proteins.
What are the possible effects of mutant HTT on cellular metabolism?
The effects on metabolism of mutant HTT could range from the cell dealing with abnormal protein, to direct and indirect effects on the mitochondria. These could impair energy metabolism and induce oxidative damage to the cell.
Mutant HTT causes decreased transport and release of BDNF. What effect does this have?
Mutant HTT causes decreased transport and release of BDNF.
The increased stimulation of extra-synaptic glutamate receptors takes place (e.g. in the NMDA receptors).
This reduces the uptake of glutamate and leads to exotoxicity and increased susceptibility to metabolic toxic effects.
Activating microglia produces increased inflammatory activity.
