SCAs Flashcards
in what disease is SOD1 mutated? What is the role of SOD1?
superoxide dismutase 1 converts superoxide to hydrogen peroxide. it is an antixodiant. mutations in this can be found in friedreichs ataxia. A loss of this function allows for increased toxic ROS funcction in the damage of DNA nad oxidation of lipids and proteins.
Mutations are also found in ALS.
what is friedreichs ataxia
This is a reccessive form of ataxia stemming from the accumualtion of GAA repeats in the FRATAXIN gene.
the triplet repeat expansion greatly disrupts the normal production of frataxin. Frataxin is found in the energy-producing parts of the cell called mitochondria. Research suggests that without a normal level of frataxin, certain cells in the body (especially peripheral nerve, spinal cord, brain and heart muscle cells) produce energy less effectively and have been hypothesized to have a buildup of toxic by products leading to what is called “oxidative stress.” Lack of normal levels of frataxin also may lead to increased levels of iron in the mitochondria. When the excess iron reacts with oxygen, free radicals can be produced. Although free radicals are essential molecules in the body metabolism, they can also destroy cells and harm the body.
this results in increased oxidative stress as a consequence of increased ROS production and mtDNA, Lipid and protein damage,
it has also been linked to mutations in SOD1.
Usually number of GAA repeats in the frataxin gene, how does this change?
usually only repeats 7-22 times and this 100 or even 1000 times.
The number has been related to the severity and rate of disease progression.
outline a epigenetic role in fiedreich and possible therapeuticondrial dysfunctions s
HDAC inbitors increased frataxin
PimelicdiphenylamideHDACi109 (RG2833)– Increased frataxin in cell models– but has Potentially toxic metabolic by-products
• Nicotinamide (vitamin B3)– Improved frataxin levels in Phase IIb clinical trial (promising showed sustained improvement and plays role in switching back on gene)
What are the core symptoms of SCAs?
They exerience several motor deficts”
- slurred speech (dyarthria)
- problems with walking gate very unsteady
- stiif jaw, jaw distonia
- dysmetria, over or under execution of motor movements.
- clear issues with proprioception, very of balnace stuggling to rebalance if give a jolt to the back.
- INTENSION tremor- shake when moving
- Abberant eye movements- Slow and Resticted.
What is thought to cause the intention tremor in SCA.
This has been shown to be caused by lesions to Pontocerebellar connection from the Cerrebellum>dentate nucleus>ventral and anterior and ventral lateral thalamic nuclei> motor cortex.
This could stem from cerebellar atrophy which occurs in SCAs
What is the undelrying pathological and genetic cause of SCAs.
The underlying pathology is the degeneration of inhibitory purkinje neurons in the Cerrebellum.
these are found in the folia. Over the course of the disease they will progress from PN dysfunction showed by hypoactivity and more severe lack with neurodegen. Dysfunction is linked to issues with Calcium dysregulation through the Mglur pathway.
This is caused by mutations in several genes relating to the MGLUR pathway (IP3R,PK3), Calcium homeostasis (Cav2.1, Cav B4 accesory subunit,IP3R) and many in Ataxin. alongside SNPs and deletions A hall mark of the many of these is the presence of the triplet nucleotide repeat expansion CAG seen in (SCA 1,2,3,6,7,17)
This is normally between around 22 and anything above 32 is pathological.
In terms of Ataxin CAG exansiosn do not cause loss of function, they drive toxic gain of function. as demonstrated in a study by HANSEN et al 2012
-studying a trasgenic mouse line expressing Ataxin 2(mutated in SCA2) 127q.
- showed progressive decline in motor dysfunction as rotarod test lantency to falling.
-showed progressive degeneration as PN staining fell along side the branching of purkinje neurons.
-showed progressive decline in PN firing rate showing a reduction in signature pacemaking activity.
This is NOT seen in ataxin KO showing this is purely a toxic gain of function.
What is the inheritance pattern of SCAs
This is a autosomally dominat inherited disease.
provide evidence that SCA2 ataxin2 CAG expansions pathogenic apects are a cause of toxic gain of function and not LOF?
In terms of Ataxin CAG exansiosn do not cause loss of function, they drive toxic gain of function. as demonstrated in a study by HANSEN et al 2012
-studying a trasgenic mouse line expressing Ataxin 2(mutated in SCA2) 127q.
- showed progressive decline in motor dysfunction as rotarod test lantency fell.
-showed progressive degenration as PN staining fell
-showed progressive decline in PN firing rate showing a reduction in signature pacemaking activity.
This is NOT seen in ataxin KO showing this is purely a toxic gain of function.
What impact does larger repeat number have of SCA?
This reduces the age of onset. the ranges fro this varies between SCA subtypes.
What is the role of the cerrebellum and purkinje neurons in movement and in which disease is this a core part of disruption
This is severely effected in SCAs.
In this the purkinje neurons found in the folia of the cerrebellum are degenated.
-The are inhibitory neurons that inhibit motor neurons.
-They have a sustained auto-regulatory (no inputs needed) firing rate which is relatively high. This is modulated by excitatory Parralel fibres)
-Thus they regulate movement hrough pauses in activity allowing active firing of the MNs.
This is shown in a study by LEE et al - they specifccaly expressed orange light sensitiv optogentic receptor archeorhodpin in the PNs of mice and stimulated them to inhibit the PNs trasniently and found this could induce lower legs movement.
The cerrebellum- key role in fine tuning complex moevemnt on a fast time scale
- Communicates with the brain stem centres including: ascending motor fibres, vestibular nuclei, and motor cortex. also Recieving inputs from the reticular nuceli and spinal nerves.
- Hence it takes into account, somatosensory, visual, auditory, proprioceptive, vestibular, feedback motor inputs.
Provide support for the role of ataxin CAG mutations in SCA?
-several monogenic forms stem from CAG repeat expansions i the ataxin gene- SCA1,2,3,7
- Ataxin CAG exPansion dthey drive toxic gain of function. as demonstrated in a study by HANSEN et al 2012
- studying a trasgenic mouse line expressing Ataxin 2(mutated in SCA2) 127q.
- showed progressive decline in motor dysfunction as rotarod test lantency fell.
- showed progressive degenration as PN staining fell
- showed progressive decline in PN firing rate showing a reduction in signature pacemaking activity.
- Ataxin repeat expansions have been shown to stunt PN branching
- Meera et al- in ATXN127q model, mGlur induced PN firing was enhanced and Caclium transient currents were much larger than controls.
- SCA1 model q82 aslo showed progressive reduction in pacemaking activity (Hourez et al)
SCA2 model q58 with PN specific expression of muatnt atxin reported impaired firing and reduced firing frequency.
Calcium dysregulatiuon has been linked to potential excitotoxicty.
- in ATXN2q 58 mutants in cell cultures have been shown to have enhanced calcium basal to peak shifts.
- Ataxin 1 and 3 mutants have been shown to bind IP3Rs ad potteniate calcium release.
*Meera et al- in ATXN127q model, mGlur induced PN firing was enhanced and Caclium transient currents were much larger than controls.
Rouseaux et al 2018, has relates capicua’s association with ataxin1 to be implicated in SCA1. c
- corss breeding capciua KO with SCA1 mice seeing dose depednant reduction in ataxin 1
- Cic reduction was able t rescue the motor deficits of SCA1 mice testsed on rotarod appaeratus.
- Further study was able to relate ataxin 1 muations causing varying effects on cic, binding stronger or weaker t some targets. CIC KO simply reversed the Hyper repression. SO ataxin could be working through the disruption of genetics also.
Varying support for the importance of PN pacemaking dysfunction (at least 3) and MGlur link caclium dysregulation.(at least 2+2)
PN hypofunction.
-several monogenic forms stem from CAG repeat expansions i the ataxin gene- SCA1,2,3,7
- Ataxin CAG exPansion dthey drive toxic gain of function. as demonstrated in a study by HANSEN et al 2012
- studying a trasgenic mouse line expressing Ataxin 2(mutated in SCA2) 127q.
- showed progressive decline in motor dysfunction as rotarod test lantency fell.
- showed progressive degenration as PN staining fell
- showed progressive decline in PN firing rate showing a reduction in signature pacemaking activity.
- Ataxin repeat expansions have been shown to stunt PN branching
- SCA1 model q82 aslo showed progressive reduction in pacemaking activity (Hourez et al)
SCA2 model q58 with PN specific expression of muatnt atxin reported impaired firing and reduced firing frequency.
*Another form,SCA5, models in a beta III spectrum KO rodent show a loss of resurgent voltage sodium gated channel currents which is key o pacemaking activity
Overactivity of channels
Calcium dysregualtion and mGlur dysfunction.
Hyperactivity of pathway and excitiotoxic caclium release.
*- in ATXN2 q 58 mutants in cell cultures have been shown to have enhanced calcium basal to peak shifts.
- Ataxin 1 and 3 mutants have been shown to bind IP3Rs ad potteniate calcium release.
- Cav2.1 mutations can cause ataxia
- Meera et al- in ATXN127q model, mGlur induced PN firing was enhanced and Caclium transient currents were much larger than controls.
- Studies introducing IP3 phophatases to mouse models have shown improvemnet in ataxic behvaiour supporting the idea of a hyperactivity of caclium channels.
hypofunction of the pathway.
LOF mGLUR pathway
- PN specific KO of mGLUR cause ataxia and use of Autoantibodies cause paraneoplastic -cerrebellar ataxia. Hence, function is key to stopping ataxic symptoms.
- use of allosteric modulators to boost mGLUR function in a SCA153Q MOUSE MODEL can imporve ataxic behaviour.
- several parts of the mGlur Pathway cause ataxia if disrupted.
- PKC muations SCA14
- IP3R which activates ITPR1 in SCA15
*Studies shave shown a gradual decline in Mglur receptors over time using wetern blot analysis but this also correlated with decreases in dendritic spine density, looking at the expression on the remiaing spines, the mglur expression was normal. Hence, This decline may not be the cause.
The evidence surrounding SCA can both implicate reductions or decreases in the mGlur cascade in pathogenics. try to reconcile this discussing the 2 key feedback mechansims involved in the mGLUR-Ca2+ hypothesis.
What is clear is mGluR dysfucntion and calcium dysregulation are key.
To reconcile this you have to move forward with the assumtpion that the multitude of mutations and dyfunctions observed have the end result of a gradual fai;liure of PNs to regulate calcium levels
The consequentil elevelated caclium levels can the drive excitiotoxicty and dmage via the Mglur-caclium excitotoxicty pathway via two postive feedback loops.
Calcium levels have been shown to pottentiate Mglur function. this involves acting at Mglur channels and early points in the pathway like TRPC3 channles.
Caclium also feedbacks back o calcium release via IP3Rs to casue CICR. (bell shape like feedback (some point is inhibitory)
These indepednat feedback patwhays imply a strong and multifaceted pottentiation exterted by caclium.
hENCE WHY THEY ARE TOUGHT TO EXACERBATE THE CONDTION.
outline the mGLUR Gq pathway implicated in SCA?
The Gq alpha particle will activate photolipase c which is trun cleaves PIP2 to from IP3 (inositol-1,2,3- phosphate) and DAG (di acyl glycerol).
Ip3 will go on to act on IP3 rceptors on intracelular calcium stores driving the release of calcium ino the cell which results in CICR and PKC activation.
IP3 has a particular high expression in PNs.