what behvaioural deficits are observed in the FTD p3015 mutated MAPT model shown in 2012 MWM study.
This study investigated the impact on MVM training in 2012.
They reported cognitive deficots in spatial learning and memory.
motor abnormalities such as clasping when raised by te tails and limb weakness.
This could be applied also to deficts in AD
briefly decribe the FTD-ALS spectrum in terms of symptoms and common underlying genetic causes?
Growing evidence suggests that FTD and ALS may be 2 extremes of a sepctrum of disease. This stems from the heavy role of C9orf72 mutations in both diseases and in the cause of FTD-MND patients. Ths is primary linked to TDP-43 patholgy. This pathology can be seen in motor areas in dominantly FTD patients.
In terms of symptoms 50% of ALS pateints present with some behavioural abnormality and a subset will develop the behvaioural vairant of FTD. (5%)
This can be linked further to overlaps in pathology, With TDP-43 inclusions being a primary pathogenic factor in ALS whislt also contibuing to around 50% of FTD cases. In addition, alsthough rare in both diseases, inclusions of Fusion in sarcoma (FUS) intarcellular inclusion can be seen in both diseases.]
This suggests a underlying overlap in the aetiology of each disease.
What are the main clinical presentations of FTD? briefly expalin them
FTD patients present with 2 distinct phentypes.
Behvioural variant- defined by changes in personality and deterioration of emotions and Social conduct.
Progressive aphasia FTD- this is linked to issues of speech and is defined by 2 variants.
- Non-fluent- defined by issues with the production of speech and other orofacial deficits, and facial actions like swallowing.
- semantic variant- defined by issues undertsaning the meaning and comprehension of words linked to deficits in semnatic memory.
The variations can be linked t the unique ASSYMETRIC atrophy seen in FTD and the sights of atrophy.
BV- observe deterioration in the fronto-insular cortex (linked to sense of ones emotios and self) and Anterior cortex (linked to output of emotions and emotional control.
-degen is paritcuarlly revalent in the right hemispehere where the ACC acts as part of the SALIENCE circuit of emotions with links to emotional areas like the hypothalamuds, amygdala. these are dgeenerated early on. hence, explaining behavioural and emotional phenotype.
- degen in progressive aphasia is asscoaited with the left hemisphere., The left hemisphere is refferered t as the dominant hemisphere due to its roles in speech.
- temporal lobe in semantic
- premotor regions in non-fluent
How might assymetric degeneration in FTD explain variations in clinical presentations?
The variations can be linked t the unique ASSYMETRIC atrophy seen in FTD and the sights of atrophy.
BV- observe deterioration in the fronto-insular cortex (linked to sense of ones emotios and self) and Anterior cortex (linked to output of emotions and emotional control.
-degen is paritcuarlly revalent in the right hemispehere where the ACC acts as part of the SALIENCE circuit of emotions with links to emotional areas like the hypothalamuds, amygdala. these are dgeenerated early on. hence, explaining behavioural and emotional phenotype.
- degen in progressive aphasia is asscoaited with the left hemisphere., The left hemisphere is refferered t as the dominant hemisphere due to its roles in speech.
- degen in temporal lobe semantic
- degen in premotor regions in non-fluent.
How can FTD be distinguished from AD?
A basic and unaccurate split is that FTD is a form of early onset dementia whislt AD is primarily late onset.
Better are:
Symptoms- FTD patients tend to have mainatined cognition early on only displaying mild memory deficits
-AD patients tend to have maintained empotional repsonses.
Marker- CSF samples can be applied to look for AD markers like Amyloid beta 40/42
How can FTD be distinguished from Psychological disorders?
Pyschological diseases
These can be distinguished use MRI, phentoypic copies of FTD will NOT have Atrophy.
What are the 3 key pathologies in FTD? outline them?
Tau pathology:
- shared in common with AD this is seen in 40% of FTD patients
- Stems from MAPT unlike in AD mutations here can cause FTD.
- toxicity associted with the hyperphophoryaltion of TAU resutling in the formation of paired helical fragments of TAU and microtubules. this results in large insoluble deposits as NFTs.
- This leads to a loss o tau funcion in stabilising Microtubules and a defficient in Micro tubuless having larg impats on their roles in neurofilaments and axonal transport.
- The subsets of FTD linked to TAU dysfucntion can be related to vaired expression of the carboxy terminal repeats that bind the MTS. 3R (causes Picks disease) or 4R (4 subtypes of tauopathy disease, progressive supranuclear palsy: Cortical basal degeneration, globular glial tauopathy, agyrophillic grain disease)
- Cotical basal pattern on deposition primary in white and grey matter of cortical areas and the Basal ganglia could explain parkinsonisms in FTD patients.
Studies performed in Neural stem cells have implicated MAPT muations in dysfunction endocytic trafficking.
- Studies in I FTD MAPT mutant patients have also reported issues with alternative splicing at exon 10 going to incresed 4R varaint. This is recapitualted in IPSCs thus these are vaible models to investigate the effectof the 3r-4r switch.
TDP-43 this is responsible for 50% of cases and is the most common pathology in ALS.
- TDP-43 is the Transactive-response DNA binding protein. It can be seen to traffick in and out of the nucleus playing key roles in RNA transcription splicing and stabilisation of long introns.
- In disease it accumualtes in cytoplasmic inclusions and neurotic tangles which are extracellular leading to a LOF in the nucleus and cytoplasmic Gain of function.
-Note- work in drosophilla has reported: LOF of TDP-43 has been related to motor abnormalities in larvae and decreased boutons at NMJ. Over expression of human trangene in drosophila also led to reduced boutons and dendritic branchhing. So both linked to toxic dysfcuntion of synaptic trasnmission that cause neurodegenration. Synaptic dysfunction is one of he early pathologies of ALS. skewed to wards LOF as theyre removed from fucntional location.
Ling et al 2015- Showed that CRE=ER controlled KO of TDP-43 led to loss of splicing of cryptic EXONs tat led to disrupted MRNA translation and the formation of several abberant porteins in mouse embryonic stem cell. Restoring splicing of these expns was able to prevent cell death in these lines.,
there are 4 subtypes distingyuishable by the layers of depostion and the forms of inclusios involved.
1- this primay effects layers 1 and 2 and has an abundance of cytoplasmic neuronal nclusoi=ion and SHORT neurotic tangles. (primary related to BV and NF Phenotype and C90rf72 and GRN mutations)
2- This effects all layers and consists of mainly cytoplasmic inclusions. (Best linked with bv PHENOTYPE and FTD-MND, thus C9orF72)
3- This effects predomiantly the first 2 layers involving LONG neurotic tangles. (This is est associated with the Semantic phentoype)
4- this unquiely has Nuclear inclusions and it related to the IBMPFD (Inclusion Body Myopathy early onset Paget Disease FTD)seen in rare VCP mutations.
In a smaller 5-10% of cases Tau and TDP pathology is rarer.
FET-FTD- this is related to dysfucntion in a family of proteins
- Fusion in sarcoma (FUS) . Ewing sarcoma, and TATA-box DNA/RNA binding factor 15
- FUS is heavily related to psychotic symptoms and represents another overlap with ALS wit this also being a rarer pathology found there.
UPS- Ubiqutin protein system can also be dysfucntional. This isvery rare and identiffied in the rare muatations of CHMP2B. This protein in related to the activity of the multivesicular body. Staining here commonl shows TDP-43 and FUS inclusions.
How can tau depostion been used to vary between diseases sharing tau pathology?
We can look at the wetsern blot identified bands expressed, and look at the location of depostion.
For example signs of Astrocyte plaques are a hall mark of Cortical basal DegenerATion asocciated to 4R tau.
FTD is 30% fammilial and 70% sporadic, outline the 3 main genetic mutations? link to disese mechanism
MAPT- microtubule associated protein TAU.
- This protein is key to the stabilisation of microtubules, thus playing a key function in axonal transport.
- unlike in AD these mutations are associated with the causation of the disease,.
- stduies in neruonal stem cells, have implicated dyfunctional endocytosis as an infleunce of this mutation.
- most notably this is associated with the formation of hyperphophorylated tau that froms large insoluble cytoplasmic aggregations called NFTs.
- LOF is the main cause of disease.
- Studies in I FTD MAPT mutant patients have also reported issues with alternative splicing at exon 10 going to incresed 4R varaint. This is recapitualted in IPSCs thus these are vaible models to investigate the effectof the 3r-4r switch.
Progranulin (GRN)
- this protein is produced by microglia in response to insult, this leads to endocytosis by sortilin receptors on neurons and susqeent lcoalisation to lysosmes via intercation with lysosomal proteins TMEM106B. here it is key to lysosomal function.
- Its role in lysosomal function is demonstrated in studies of pateints.
- homozygous children presented with neuronal ceroid lipofuscinosis, a lysosomal storage disroder in which abnormal lipopigemtns in lysosomes leads to severe neruodegeneration.
- Meanwhile, elders with Hetrozygous muations and thus haploinsuffiency, xpereinced FTD.
- This is primarily asscoiated with type1 FTD-TDP patholgy, and demonstrates a link to lysosomal dysfunction in FTD.
- TMEM106B has been identified as a RISK factor for FTD, which FTD sufferers with mutation displaying a shorter disease course.
C9orF72- this is the core link between FTD and ALS, being a large genetic contributor in both cases.
- The GGGGCC repeats can be translated in either direction in any reading frame producing 5 different transcripts. (GP,GA,GR,PR,PA)
- it is predminatly asscoiated with FTD-TDP type 1 and 2 pathology, and thus unsuprisingly, behvaioural and non-fluent phenotypes, alongside, psychosis, MND.
- Was discovered in the FTD-MND phenotype.
- the notmal function of the disease is unknown, allthough some reaserc has pointed towards a role in LYSOSOMAL biogenesis and autophagy by interacting with GEF, serine threonine kinases Like TBK1 (autophagy) and RAB GTPases)
- Mutations are the results of a hexanucleotide repeat expansion, from around 22 repeats of 100s -1000 IN SOME pathogenic cases. This is a GGGGCC repeat
The are 3 mechanisms by which they believe this could be toxic.
-LOF th natural function is unkown but losing this could be toxic.
*KD studies have shown that this will inhibit the INDUCTION of autophagy that correlated with increased P62 AND TDP inclusions. pottentially a link to increased TDP.
*Ideas arre supported by SHI et al (2018) that show in patient derived and Crispr/CAS9 KO IPSC there is reduced endocytosis and vesicular trafficking.
*However= in CRISPR.CAS9 KO MOUSE MODELS, non precipitate the disease (ALS or FTD) suggesting that the haploinsuffieiciency alone does not cause the,.
ALthough, it could still contriute to excaerbate the condition through idsrupted lysomal fucntion e.t.c.
- RNA toxicty- The formation of snese and antisense RNA FOCI have been repored [primarily in the frontal cortices of ALS and FTD patients. Commonly these are foun inside NEURONAL NUCLEI. The Repeats form loop called G-quadruplexs that allow for atypical pairing, this allows for the binding of RNA-binding like TDP=43 AND FUS dirupting their function in RNA processing and trappingproteins in the nucleus. These can trap RNA in nucleus
- PROTEIN TOXICITY - the long repeat can cause an abberant processing of RNA called REPEAT ASSOCIATED NON-ATG translation (RAN-translation). This forms toxic DIPEPTIDE REPEAT PROTEINS, which are aggregation prone and interfere with RNA processing.
MIZIELINSKA et al 2014
-Support from study in FTD studies in drosophilla.
-expressed pure RNA and RNA-only forms in models. They showed via FISH that both could form RNA foci, but in IMMUNOBLOTTING they showed Pure RNA ALONE could cause DPRs.
-Using eye degeneration as a marker of neurodegen> Those soley expressing GGGGCC repeat expanded RNA (no protein) did not cause neurodegen. Whilst models only expressing pure RNA did cause degeneration suggeststing dipeptide repeats mediates toxicity.
- To see what was the cause of this they expressed a PROTEIN ONLY model differentiating between 2 codons in the REPEATS the sample those RICH IN ARGININE poly GLYCINE-ARGININES AND PROLINE ARGININES VS poly Glycine and proline alanines. They showed those
ARGININE RICH REPEATS DPRs alone caused increased eye degeneration.
Hence the arginine rich DPRs would seem to be the cause of C9orF72 neurotoxicity.
However, in posrt-mortem study the pattern of TDP pathology much btter tracks neruodegenration and is NOT common seen with DPR inclusios.
Given the links of DPRs to neruodegen in mouse models, it is likely DPR acts upstream fo TDP expalining its better correlation with DEGEN in psot-mortem studies which tend to represent end stages of the disease.
However, Knockin mouse models of C9orf72do not show TDP iclusions. despite observing motor, Cognitive defects with degeneration.
The downstream effects of C9orF72 DPRs have been implicated partiucuarly in issues with Nucleocytoplasmic transport.
- Zhang et al showed that the expression of poly GRs and PRs was able to induce increased stress granule formation that drove NCT disruption.
- He equally showed using ASOs to sequester C9orf72 could reduce NCT defects and TDP mislocalisation.
Name 3 rarer muations seen in FTD?
CHMP2B- this is associated with FTD-UPS. muattions where identified in a danish family with autosomal dominant FTD.
- Mutations have been identified on chromosome 3 that drive the fromation of a carboxy ternminal truncated portein.
- Its usualy function is in the sorting of proteins to the lysosomes for degredation.
- This suggets a LOF given the frequent links to lysosomal function in FTD.
- UPS likely breaksdown aggreagates as TDP-43 inclusions are ubiquitin psoitivie so issues ould prevent this.
VCP- This protein is involved in Protein homeostaiss and muation of its loci on Chromosome9 have been associated with FTD. inm particular the type 4 variant of TDP-43 linked FTD (IMBPFD)
- There is a large overlap here with other diseas. 1 being body myopathy which is a autosomal dominat disease conferring muscle weakness. 32% of these patients develop FTD with language and behvaioural dysfunction.
Ritson et al 2010, showed that expressing disease mutant forms of VCP ectopically led to photreceptor degen in drosophilla. This was enhanced by co expressing wild type TDP-43 and decreased by KD of TDP. links to ideas that issues with [proteoostasis cause toxicity linked to reduced breakdown of TDP=43 aggregates.
TARDBP- this is the TDP-43 GENE, recently the first case of a TDP-43 muation in FTD without MND was found. Before this TDP-43 muattions had been linked to sporadic cases of C90rf72 and GRN miutations.
What is the potential links between TDP-43 and C90rF72 DPR pathology?
C9orF72 exmapnsions are primary seen with TDP-43 inclusions in FTD and ALS.
However, in posrt-mortem study the pattern of TDP pathology much btter tracks neruodegenration and is NOT common seen with DPR inclusios.
Given the links of DPRs to neruodegen in mouse models, it is likely DPR acts upstream fo TDP expalining its better correlation with DEGEN in psot-mortem studies which tend to represent end stages of the disease.
Outline the characterisitic of C9orF72 repeats
C9orF72- this is the core link between FTD and ALS, being a large genetic contributor in both cases.
- The GGGGCC repeats can be translated in either direction in any reading frame producing 5 different transcripts. (GP,GA,GR,PR,PA)
- it is predminatly asscoiated with FTD-TDP type 1 and 2 pathology, and thus unsuprisingly, behvaioural and non-fluent phenotypes, alongside, psychosis, MND.
- Was discovered in the FTD-MND phenotype.
- the notmal function of the disease is unknown, allthough some reaserc has pointed towards a role in LYSOSOMAL biogenesis and autophagy by interacting with GEF, serine threonine kinases Like TBK1 (autophagy) and RAB GTPases)
- Mutations are the results of a hexanucleotide repeat expansion, from around 22 repeats of 100s -1000 IN SOME pathogenic cases. This is a GGGGCC repeat
The are 3 mechanisms by which they believe this could be toxic.
-LOF th natural function is unkown but losing this could be toxic.
*KD studies have shown that this will inhibit the INDUCTION of autophagy that correlated with increased P62 AND TDP inclusions. pottentially a link to increased TDP.
*Ideas arre supported by SHI et al (2018) that show in patient derived and Crispr/CAS9 KO IPSC there is reduced endocytosis and vesicular trafficking.
*However= in CRISPR.CAS9 KO MOUSE MODELS, non precipitate the disease (ALS or FTD) suggesting that the haploinsuffieiciency alone cause the disease
ALthough, it could still contriute to excaerbate the condition through idsrupted lysomal fucntion e.t.c.
- RNA toxicty- The formation of snese and antisense RNA FOCI have been repored [primarily in the frontal cortices of ALS and FTD patients. Commonly these are foun inside NEURONAL NUCLEI. The Repeats form loop called G-quadruplexs that allow for atypical pairing, this allows for the binding of RNA-binding like TDP=43 AND FUS dirupting their function in RNA processing and trappingproteins in the nucleus. These can trap RNA in nucleus
- PROTEIN TOXICITY - the long repeat can cause an abberant processing of RNA called REPEAT ASSOCIATED NON-ATG translation (RAN-translation). This forms toxic DIPEPTIDE REPEAT PROTEINS, which are aggregation prone and interfere with RNA processing.
MIZIELINSKA et al 2014
-Support from study in FTD studies in drosophilla.
-expressed pure RNA and RNA-only forms in models. They showed via FISH that both could form RNA foci, but in IMMUNOBLOTTING they showed Pure RNA ALONE could cause DPRs.
-Using eye degeneration as a marker of neurodegen> Those soley expressing GGGGCC repeat expanded RNA (no protein) did not cause neurodegen. Whilst models only expressing pure RNA did cause degeneration suggeststing dipeptide repeats mediates toxicity.
- To see what was the cause of this they expressed a PROTEIN ONLY model differentiating between 2 codons in the REPEATS the sample those RICH IN ARGININE poly GLYCINE-ARGININES AND PROLINE ARGININES VS poly Glycine and proline alanines. They showed those
ARGININE RICH REPEATS DPRs alone caused increased eye degeneration.
Hence the arginine rich DPRs would seem to be the cause of C9orF72 neurotoxicity.
However, in posrt-mortem study the pattern of TDP pathology much btter tracks neruodegenration and is NOT common seen with DPR inclusios.
Given the links of DPRs to neruodegen in mouse models, it is likely DPR acts upstream fo TDP expalining its better correlation with DEGEN in psot-mortem studies which tend to represent end stages of the disease.
However, Knockin mouse models of C9orf72do not show TDP iclusions. despite observing motor, Cognitive defects with degeneration.
The downstream effects of C9orF72 DPRs have been implicated partiucuarly in issues with Nucleocytoplasmic transport.
- Zhang et al showed that the expression of poly GRs and PRs was able to induce increased stress granule formation that drove NCT disruption.
- He equally showed using ASOs to sequester C9orf72 could reduce NCT defects and TDP mislocalisation.
