Nervous System Ageing LT3 Flashcards
What symptoms occur in frontotemporal dementia (FTD) and why?
Progressive degeneration of the frontal and temporal lobes of the brain = cognitive function decline and characterized by personality and behavioural changes, as well as gradual impairment of language skills
Resulting in:
Poor judgement, loss of empathy
Socially inappropriate behaviour and lack of inhibition
Repetitive compulsive behaviour
Inability to concentrate or plan
Frequent, abrupt mood changes
Speech difficulties, memory loss, problems with balance/movement
How are ALS and FTD related?
Overlapping clinical and genetic signature = share dysregulation in TDP-43 and FUS/TLS
Grandparents with ALS can give rise to grandchildren with FTD or ALS-FTD
Do both TDP-43 and FUS/TLS need to be present for neurodegeneration to occur?
No, neurodegenerative processes driven by FUS/TLS mutations are independent of TDP-43 mislocalization
What are the roles of TDP-43 and FUS?
RNA/DNA binding proteins
Transactive response DNA-binding protein (TDP-43) = main component of ubiquitinated protein aggregates found in sporadic ALS patients and in patients with FTD
What occurs for TDP-43 to cause pathology?
Under normal conditions, TDP-43 is mainly localized within the nucleus
Abnormal TDP-43 distribution such as neuronal cytoplasmic or intranuclear inclusions and dystrophic neurites, as well as glial cytoplasmic inclusions have been reported.
A very curious, and mechanistically unexplained, aspect of TDP-43 pathology is a significant TDP-43 nuclear clearance in a proportion of neurones containing cytoplasmic aggregates, suggesting that pathogenesis may be driven, at least in part, by loss of one or more nuclear TDP-43 functions
What occurs for FUS/TLS to cause pathology?
Like TDP-43, FUS/TLS is mainly nuclear, with lower levels of cytoplasmic accumulation detected in most cell types.
Postmortem analysis of brain and spinal cord from patients with FUS/TLS mutations found abnormal FUS/TLS cytoplasmic inclusions in neurons and glial cells
How does TDP-43 regulate cryptic exons?
Represses splicing of nonconserved cryptic exons
What occurs when TDP-43 is depleted, and what can we conclude from that?
When TDP-43 was depleted from mouse embryonic stem cells, these nonconserved cryptic exons were spliced into messenger RNAs = often disrupting their translation and promoting nonsense-mediated decay.
Enforced repression of cryptic exons prevented cell death in TDP-43–deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.
What accounts for selective neuronal/regional vulnerability in NGDs? What does this mean?
Q: Why are only some neurones in specific areas expressing these mutations?
A: Glial cells are different in different brain regions = could cause regional vulnerability
How does glial dysfunction contribute to neurodegeneration and ageing?
There is a connection between glial cells and neruones
What accounts for age-dependency? So, could anti-ageing approaches be used to prevent/reverse NGD? What does this mean?
Why does it only manifest when we are older?
Because of age-dependency, could anti-ageing approaches be used to prevent/reverse neurodegeneration
How is the mechanism of TDP-43 and FUS/TLS causing ALS and FTD figured out?
Use disease-linked genes to understand basic biology
Investigate the mechanisms by which disease may arise
Use mouse model to mimic the ALS and FTD
1. By disease mutations
2. Loss-of-fuction studies (condition KO) = cell-type specific deletion
Then genomic analysis = RNA-seq from tissues, cell type, single cell
What are the functions of TDP-43 in glia?
Regulates multiple RNA metabolic processes, including transcription, alternative splicing, and RNA transport in the nucleus
TDP-43 is expressed in many different cell types
Do TDP-43-mediated damages within glia contribute to neurodegeneration?
Yes
How may loss of TDP-43 in glial cells contribute to ALS and FTD?
TDP-43 loss in glial cells worsens ALS and FTD by disrupting the supportive functions of glia, promoting neuroinflammation, and increasing oxidative stress, whereas in motor neurons, it directly impacts neuronal survival and function.
What do oligodendroglia TDP-43 deletion mice develop?
Neurological phenotypes
Age-dependent motor coordination deficits and early lethality
Progressive myelin deficits in the brain in both gray and white matter of the spinal cord without gross neuroanatomical changes
What are the two potential mechanisms for demyelination?
Progressive myelination reduction likely due to combination of:
Cell-autonomous RIPK1-mediated necroptosis of mature oligodendrocytes
TDP-43-dependent reduction in expression of myelin genes
What was the difference found between grey and white matter oligodendrocytes in terms of regeneration?
Enhanced proliferation of NG2-positive OPCs within WHITE matter, but not grey matter, was able to replenish loss of mature oligodendrocyte
This indicates intrinsic regeneration difference between grey and white matter oligodendrocytes
What factors cause demyelination?
Cholesterol biosynthesis regulated by SREBP(SREBF)
Cholesterol is key molecule needed to make myelin
Why does CNS cholesterol need to be made locally?
As soon as BBB is formed cholesterol cannot pass through to the brain
What makes cholesterol in CNS?
Astrocytes and oligodendrocytes
What is horizontal cholesterol transfer?
Cholesterol transported between neurones and glia
Cholesterol transported as forms of LDLs containing ApoE = recognized by LDLRs
How does TDP-43 regulate cholesterol metabolism?
TDP-43 is required for expression of SREBF2
What is SREBF2?
Master TF for cholesterol homeostasis
When cholesterol is high, SREBF2 stays in ER
When cholesterol is low, SREBF2-SCAP is cleaved so SREBF2 can enter nucleus = causing cholesterol biosynthesis and uptake
What happens to SREBF2 when TDP-43 is deleted?
Without TDP-43 = disruption of cholesterol metabolism
TDP-43 binds the same mRNA that SREBF2 regulates, so without it = reduction of this mRNA
Also, reduction in LDLR mRNA and proteins = less cholesterol uptake
Which is more important in the TDP-43/SREBF2 cascade?
SREBF2 because when it was reintroduced then cholesterol levels are restored
What happens when TDP-43 in Schwann cells is deleted?
Myelination remains intact
BUT conduction velocity is reduced
What is the role of the paranode in Schwann cells?
In the regions directly adjacent to the nodes, termed the paranodes, loops of myelin form a tight, septate-like junction (SpJ) with the axonal membrane.
This junction provides scaffolding within the axon to compartmentalize molecules within the axon and restrict the movement of ion channels within the axonal membrane
What happens to the paranode of Schwann cells in TDP-43 deletion mice?
Paranode is lost
Paranode usually made of 3 proteins = Nfasc, Caspr, Contactin
How does TDP-43 depletion affect Nfasc in Schwann cells?
Leads to incorporation of a cryptic exon of Nfasc in Schwann cell
The incorporation of these cryptic exons can produce abnormal neurofascin isoforms that may disrupt the normal functions of Schwann cells, such as myelin sheath formation and maintenance of the paranodal region
What correlates with decrease in neurogenesis?
An increase in chemokines during age correlates with decreased neurogenesis
What effect does exposure to CCL11 have?
Inhibits neurogenesis = impairing learning and memory
What was an isotype used for?
Control antibody
