Neurobiology and neurogenetics Flashcards
Protein synthesis
a) RNA polymerase
b) transfer RNA (tRNA)
c) Ribosome
d) Post-transcription
e) Peptide and hydrogen bonds
https://www.youtube.com/watch?v=gG7uCskUOrA
https://www.youtube.com/watch?v=bKIpDtJdK8Q
a) - RNA polymerase (with help of transcription factors) binds to the ‘promotor’ (start of genetic sequence), unzips the DNA and forms a sequence of pre-mRNA from the ‘antisense (template) strand’* from free bases in the nucleus of the cell.
- Pre-mRNA then undergoes some changes including splicing, capping and addition of poly-A tail before it can leave the nucleus
- This whole process is TRANSLATION
- the DNA sequence determines this mRNA sequence but note they are not identical as DNA is double strand (base pairs) whereas mRNA is single stranded
b) - Bind mRNA via anticodons (nucleotide bases), which bind the codons of mRNA
- TRANSFER the mRNA and amino acids to the ribosome
c) Ribosomes bind to mRNA and read the sequence (3 bases at a time) to TRANSLATE into a chain of amino acids to form a protein
d) - Folding into functional protein
- Changes / activation via phosphorylation or adding carbohydrate groups
e) - Adjacent amino acids linked by peptide bonds
- Folded protein 3D structure held together by hydrogen bonds
DNA
a) Exons and introns
b) How are exons and introns divided?
c) How long is typical gene?
d) What are nucleosomes, histones and chromatin?
e) Codons, including start and stop
a) - Exons - coding regions
- Introns - non-coding regions of genes
b) RNA splicing
c) 10-50,000 base pairs (though can range from a few hundred to 2 million)
d) - Nucleosomes are the basic subunit of DNA, consisting of a strand of DNA wrapped around 8 histones
- Histones are proteins that DNA wind DNA into its structure (act as spools)
- Chromatin is the substance that makes up chromosomes (DNA + protein)
e) - A trinucleotide sequence of RNA/DNA (3 bases) that code for a specific amino acid
- In eukaryotes, start codon is always AUG and codes for methionine
- There are 3 different stop codons
How ASOs work
-
DNA methylation
-
RNA
a) vs DNA
b)
a) - Ribose instead of deoxyribose
- Uracil instead of thymine
Protein sequestration.
a) what is it?
b) why it happens
a protein, or a group of proteins, is temporarily isolated or removed from its normal cellular environment and rendered unavailable for its usual functions.
b) - can be part of normal regulatory function
- happens when protein aggregates form, causing cellular dysfunction
- some viruses can sequester host proteins to allow viral replication
Cytosolic heat shock response.
a) what is it?
b) how is it brought about
a) Protective cellular process in the cytoplasm involving upregulation of heat shock proteins like HSP70 and HSP90 that prevent protein misfolding, refold denatured proteins, and prevent protein aggregates to maintain normal cellular function in the context of stresses like heat and oxidative stress
b) In response to heat/other stress, transcription factors like heat shock factor 1 (HSF1) are activated to activate transcription of genes for HSPs
TDP-43 proteinopathy
a) which common genes are not associated with this
b) usual function of TDP-43
c) how it causes disease
a) SOD-1, FUS
b) TDP-43 has a key role as a repressor of cryptic exon inclusion during RNA splicing, and loss of TDP-43 from the nucleus leads to inclusion of a cryptic exon in UNC13A
mRNA and reduced UNC13A protein expression, which may interfere with vesicle maturation during exocytosis and neurotransmitter
release
c) TDP-43 mislocalization
have highlighted both gain and loss of function:
- cryptic exon inclusion of UNC13A as above
- other alterations in regulation of splicing, including STMN2 gene, coding for the stathmin-2 protein which is involved in axon repair
- hyperresponsiveness to cellular stress,
- increased DNA damage
- widespread alterations in the transcriptome
- alteration in the transport of ribosomal protein mRNAs to regulate local axonal translation
Stress granules (SG)
Stress granules (SGs) are dynamic membraneless compartments
composed of mRNAs and RNA-binding proteins (RBPs) that assemble on a temporary basis to allow the cell to respond to stress by halting translation of the majority of mRNAs and directing the translation of cytoprotective proteins which allow the cell to mount an effective
stress response.
Normally SGs are highly dynamic structures, but in
the presence of age-related changes or severe cellular stress, they may form solid aggregated inclusion bodies
SGs in ALS contain multiple
RNAs and proteins and also proteins such as TDP-43 and FUS which
possess so-called low complexity prion-like domains that are prone
to aggregation
