Huntingdons Flashcards
What is the cause of anticipation and in what neurodegenerative diseases is this observed?
Anticipation is a process by which the Polyglutamine repeats (polyq/CAG) expand between generations.
This is observed in both HD and SCAs.
In HD this correlates and explains why between generations the age of onset of sufferers gets progressively earlier.
(Massey disease model)
expansions in though to occur by toxic cycles of DNA damage and repair. Hence, why several risk factors for HD are associated to DNA repair Chr3-MLH1 (Mismatch repair) Chr5-MSH3-(Mismatch repair)
expansion is enhanced when inherited from males. something that has been associated to the germ line instability of male sperm.
briefly discuss the involvement of medium spiny neurons in the pathology of huntingdons
medium spiny neurons make up 95% of the striatum, these neruons are selectively damged in HD.
In HD pothology the degeneration of the MSNs underpin the motor symptoms of HD, with those associated with the indirect pathway being degenrated early on causes the loss of silencing in involuntary unwated movement (chorea), and then this spreads to other MSNs later on reslting in the more parkinsonian like rigidity.
how was the Huntigitin protein structure visualised?
the Huntigtin protein was fixed to a HTT protein associated protein and the frozen to nearl absolute 0. This allowed for the visualisation of the crystal struture.
The N-terminal which is associated with the toxic exon 1 fraction and the CAG repeas is not able to be visualised so little is known how the polyq effects the structure.
Outline the background of Huntington’s disease: Genetics (protein effected), inheritance pattern, clinical symptoms and pathophysiology
Huntingtons stems from a mutation in the huntingtin protein. this stems from the expansion of CAG repeats in the gene with 40+ causing 100% chance of disease.
this has an autosomal dominat inheritance pattern so only 1 mutant allele is required.
symptoms=
There are motor, cognitive and psychiatric symptoms, as well as pathophysiological clinical features not decribed here.
Motor- CHOREA- this is semi-directed involuntary movements.
RIGIDITY- this occurs when the MSN degenration spreads to those associated woth the direct pathway later in progression.
Pschiatric- AFFECTIVE DISORDERS- patients often show depression and high suicide risk (pottentially linked to reducion in BDNF xpression)
ANXIETY/PANIC DISORDERS.
PSYCHOSIS simmilar to SCZ
Complsuions and obsessions
Cognitive- DEMENTIA= OCCURS IN 100% OF PATEINTS.
FRONTAL DEFFICIENCIES- issues with planninng, multi tasking and increased complusivity and irritatability.
issues with psychomotor drive and meotional recognition
memory and speaking is SPARRED
These symptoms often PRE-DATE motor smtoms b p to 10 years
A physiological symptom is weightloss which as been asspociated to mitochondrial dysfucntion stemming forom the transcriptional dysregulation of PGC-1 alpha function.
pathophysiology-
HD patients suffer from the degenrations of striatal MSNs. this is at first slectively associated with thos emediating the indirect striatal pathway and then this spreads to other in later stages.
The existence of intranuclear inclusions of mHTT is hall mark of the disease. overcome the export signal.
we can also observe mitochondrial dysfucntion, reduced BDNF expression (depression) and impared proteolysis due to mHTT action.
over representation of NMDA in striatal regiona n reduced glutamate uptake also observed.
what is a polyq expansion, how are they passed on and what diseases is this associated to.
The polyq expansiuon is a polyglutamine expansion due to the expansion of the triplet CAG repeat.
This is what is associated with the disruption of HTT functions in HD and the disruption of ataxin in SCAs.
Ths is inherited much like normal genes but the repeat number within the gene can expand between generations, in anticipation.
In HTT there are several variations in th number of CAG repeats, describe them and what the impact of these ranges?
in HD there is 4 main variations of the number of CAG repeats in the HTT gene.
- in normal individuals this is between 1 and 26
- 27-35 These individuals will never develop HD, However this is still suceptible to anticipation and so their children are at risk of carrying a HD inducing mutant form of HTT
- 36-39 this section has the biggest split in penotype. 36 is related to a 50% risk of HD before death and 39 is 80% risk
4- 40+ 100% risk of HD , expansion on top of this will result in an earler age of onset.
what are the 3 ways of reffering to the Huntington gene?
HD protein, HTT, IT-15
which age of onset is referred to as early onset HD, is this associated with more or less CAG repeats.
onset at the age of 20 and below is reffered to as ealy onset HD. This is associated with more CAG repeats.
What is the parent influence of the extent of anticipation in HD?
Whether the mutant HTT gene is inherited from the mum or the father has a large impact on the extent of anticipation.
The GERM LINE INSTABILITY of the male sperm results in a much larger expansion of the CAG repeat number.
likely due to their constant replication throughout life.
What is the toxic part of the HTT protein? Is this seen in post-mortem study?is it soleley this gain of function associated to disease?
There is a growing suggestion the toxic gain of function stems from the n-terminal exon 1 region of the mutant HTT protein. (MANGIARNI et al showed this expression in R/6 HD model alone could caus symptoms.)
The Exon 1 mRNA is not seen in post-mportem studies of adult HD patients this is an argument agaisnt the abberant splicing theory. HOWEVER, it can be seen in Juvenile cases of HD. one argument in that mRNA is incredibly suceptible to degredation thus expalining absence post-mortem.
HD is not solely a gain of toxic function.
performed KO studies in mice showing that this was lethal. This suggests that a LOSS OF FUnction is also involved in pathology.
(normal function has been related to endocytosis, vesicular transport, autophagy, cell division and transcriptional regulation)
also this can be linked to the BDNF downregulation as mutant HD fails to regulat REST inhibition of expression.
outline to the 2 main HD mouse models and there differences
here are 2 mouse models>
One focusses on the Exon1. this was created in a study by MANGIARNI ET AL. the specificall express the toxic exon 1 shwoing that tis was suffieicent to induce a HT like phenotype. this is how the theory that this was essential t the toxic function came from (THIS IS THE R/6 HD model.
other models Knock in CAG expandsed repeats t normal HTT gene. this created a more subtle slowly prgressing HD phenotype.
the R6 HD and q150 knockin mice both shows similar end stage phenotypes. they only differ on age of onset and progression. This may suggest that the toxicity of the q150 knockin stems from this same abberant splicing but only differes by abundance and rate of accumulation of exon1 fragments. suggesting this is the primary toxic HTT species.
Outline the two theories by which the toxic HTT (Huntigtin) fragment forms? include questions raised from post-mortem study?
1- This suggests that the HD gene is transcribed and translated normally producing a full Htt PROTEIN. The polyq expansions on mutant Htt then causes the porteolysis of the protein forming an EXON1 specific fragment.
studies have identified some proteases that may fascilitate this (caspase-3 and caspase-6)
2- This is related to abberant splicing of the mutant HTT pre-mRNA as a result of polyq expansions in the N-terminal domain. This causes the premature termination of transcription and slective snipping of exon 1 which is released and individually transcribed resulting in the formation of a toxic exon1 specifc HTT protein fragment downstream.
SATHASIVAM et al- they showed this was caused by abberat splicing. investigations in mouse models sowed the existene of unspliced exon1-intron polyadenylated mRNA solely in mutant models indicator of abberant splcing between exon 1 and 2. using transgenic mouse lines expressing the human equivalent of the gene has simmilar findings. IMMUNOPRECIPITATION and westernblot was used to show that this RNA was indeed translated to form an exon1 specific protein fragement in HD models.
They showed this was CAG dependant by showing abberantly spliced RNA in several mouse models with varying repeat lengths abover 40. was seen in all but 20 repeat model.
They investigated post mortem samples of juvenile HD paitients using RNA sequencing identifying signals that correlated with the exon1-intro1 mRNA. so it is present i human HD patients.
The exon 1 mrna is not seen in adult post-mortem brains. this sugests that the abberant splicing mech is not sginificant. however rna is inredibly suceptible to degredation possibly explaining the absence.
It is seen juvenile forms of HD.
What is the issue of genotyping the extent of CAG repeats using blood tests or sperm smaples e.t.c in HD?
SOMATIC INSTABILITY- there is variation in the stability of CAG expansions between cell types.
a blood test yielding DNA with 40 repeats might actually be found in a individual in which the exten in the neuronal population is much worse.
Moreover, sperm have a much higher instability so an individual with safe blood levels may pass on much more sevre enes to the next generation. westernblotting in sperm often produces smear of band indicatiing large variations in the extent of expansion even in thhis 1 cell type.
what is the core pathology of HD?
HD patients suffer from the degenrations of striatal MSNs. this is at first slectively associated with thos emediating the indirect striatal pathway and then this spreads to other in later stages.
The existence of intranuclear inclusions of mHTT is hall mark of the disease.
we can also observe mitochndrial dysfucntion, reduced BDNF expression and impared proteolysis due to mHTT action.
over representation of NMDA in striatal regiona n reduced glutamate uptake also observed.
what are the symptoms of HD?
There are motor, cognitive and psychiatric symptoms, as well as pathophysiological clinical features not decribed here.
Motor- CHOREA- this is semi-directed involuntary movements.
RIGIDITY- this occurs when the MSN degenration spreads to those associated woth the direct pathway later in progression.
Pschiatric- AFFECTIVE DISORDERS- patients often show depression and high suicide risk (pottentially linked to reducion in BDNF xpression)
ANXIETY/PANIC DISORDERS.
PSYCHOSIS simmilar to SCZ
Complsuions and obsessions
Cognitive-DEMENTIA= OCCURS IN 100% OF PATEINTS. FRONTAL DEFFICIENCIES- issues with planninng, multi tasking and increased complusivity and irritatability.
issues with psychomotor drive and meotional recognition
memory and speaking is sparred.
These symptoms often PRE-DATE motor smtoms b p to 10 years
A physiological symptom is weightloss which as been asspociated to mitochondrial dysfucntion stemming forom the transcriptional dysregulation of PGC-1 alpha function.
