MND and MS Flashcards
what is the most common form of MND?
amyotrophic lateral sclerosis (ALS)
overview of MND
- umbrella term for a number of different conditions
- disease characterised loss of function in both UMN in the brain and LMN in the spinal cord
- progression to loss motor neurons themselves
- progressive and currently incurable
- ultimately fatal
most common gene mutations in famial NMD?
SOD1, TARDBP1, C9ORF72
what is SOD1?
super oxide dismutase 1
enzyme that converts superoxide radicals (O₂⁻) → hydrogen peroxide (H₂O₂) and oxygen
mutant SOD1 is unstable and prone to misfolding and aggregation in spinal cord
- protects cells from superoxide raidcal (O2-) which react with anything in the cell (free radical with single electron)
- superoxide radicals important in mitochondrial electron chain
prevalence rate of familial NMD
5-10%
SOD1 explanation
protein aggregates of SOD1
if a mutation makes it very likely for SOD1 to aggregate, that is correlated with the severity of MND
(e.g aggregation propensities of SOD1 G93 hotspot mutatnts mirror ALS clinical phenotypes)
loss of control of SOD1 means loss of control of superoxide=exitotoxicity
aggregations are TF toxic
TAR-DNA binding protein 43 (TARDBP1)
low mol weight mRNA
binding protein in spinal neurons
may regulate mRNA stability, transolcation and local translation
involved in expression of microRNA therefore loss of proteins (e,g can change dendrite structure)
genrealised loss of function in spinal neurons
c9orf72 (chromosome 9 open reading frame 72)
found throughout the brain and in pre-synaptic terminals
an abnormal expansion of a GGGGCC (G₄C₂) hexanucleotide repeat in intron 1 of the gene
protein that allows mRNA to be read in its open reading frame (triplet codons discrete)
what is sporadic MND?
idiopathic (nobody knows the cause)
= 90-95% of cases
causes of sporadic MND
- protein aggregates – SOD1, TRP43 (same as TARDBP1), ubiquitin (no protein tag)
- disruption of axonal transport
- loss of glial cells – also oligodendrocytes?
- excitotoxicity which links to abnormal mitochondria/cell metabolism
- loss to white matter tracts in crus cerebri (corticospinal)
microRNA and post transcriptional regulation
microRNA=small non-coding RNA sequences
- produced as long hairpin structures and processed to produce short sections of RNA (<30 bases)
what do microRNAs bind to and what does this cause?
bind to RISC (RNA-induced silencing complex) which cleaves target mRNA and this leads to down-regulation of
protein expression
TDP-43 (TARDBP1) and microRNA
TDP-43 promotes microRNA biogenesis=drosha and dicer complexes
TRP43 knockdown=fewer neurite extensions
TF essential of growth of dendrites
what are drosha and dicer complexes?
dicer and drosha are two critical enzymes involved in the biogenesis of small non-coding RNAs, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs)
neurite outgrowth and TDP-43
neurite extension requires a delicate balance of gene expression, and TDP-43’s role in the regulation of this process is crucial
when TDP-43 is lost or dysfunctional, the proper splicing and stabilization of certain mRNAs that encode growth-promoting proteins are disrupted, leading to defects in neurite outgrowth
downregulation of microRNA-9 and TDP-43 mutations
mutation of TDP-43 reduces synaptic function which is found in FTD/ALS patients
overview of TARDP43
loss of TARDP43 function leads to lower levels of many miRNAs
microRNAs are post-transcriptional regulators
loss of TARDP43 function leads to impaired neurite outgrowth
loss of TARDP43 function leads to impaired synaptic function TARDP43 misregulation is also associated with fronto temporal dementia (FTD)
what is FUS?
FUS is a nuclear protein that participates in several RNA-related processes, such as RNA splicing, transcriptional regulation, and RNA transport.
what is FUS (fused in sarcoma) phase separation modulated by?
molecular chaperone and methylation (add/remove CH3 groups like epignetic changes) of arginine cation-pi interactiom
FUS phase separation
undergoes phase changes between
dispersed, liquid droplet and hydrogel states which allows FUS to form transient
membrane-free organelles such as
ribonuclearproteins (RNPs) in liquid state- carries RNA and protein cargoes to dendrites and axon ternimals to regulate local RNA and protein
mutations of FUS form
mutations result in hypomethylation
and the formation of a fibrillary gel
that cannot revert to a droplet leading to impaired translation
what does FUS mutate into?
gel form similar to beta pleated sheets (like alpha-synuclein and tangles)
therefore aggregations and prevention of translation link to many motor conditions
multiple sclerosis (MS) overview
- condition which can affect brain and/or spinal cord
- wide range of symptoms like problems with vision, arm or leg movement, sensation or balance
- lifelong condition but can be mild-serious disability
- possible to treat symptoms but no cure
stats about MS
- more than 100,000 people diagnosed in UK and 1 million worldwide
- commonly diagnosed at 20/30 but can develop at any age
- 2-3 times more common in women than men
cause of MS
autoimmune disease whereby immune cell target the myelin sheath surrounding axons
myeline TF becomes inflamed
- leads to damage/scarring
- loss of function
- ultimately atrophy
what is myelin produced by in the CNS?
oligodendrocytes
localisation of demyelination in MS
occurs in small regions, often in the paraventricular regions or surrounding blood vessels
TF blood cells can get into brain because of weakened BBB (T cells, B cells and macrophages)
inflammatory phase of MS
proteins in myelin look
similar to proteins
recognised as ‘foreign’
by T cells
B cells are activated to
produce antibodies
against myelin
macrophages are
induced to phagocytose myelin
sheath
degenerative phase of MS
T cells, microglia and
astrocytes produces an
excess of L-glutamate
leads to overexcitation
of oligodendrocytes
and/or neurons
induces axonal atrophy
and/or excitotoxic cell
death
overall cause of MS
de-myelination diseases are the result of auto-immune attack via ‘molecular mimicry’ where a ‘self’ protein looks very much like a
‘foreign’ one
