Lecture 5: Nucleic Acids

Huntington’s Disease

an autosomal dominant disease

what causes Huntington’s Disease

a result of the Huntington (HTT) gene, repeating codon multiple times - this codon is CAG, which codes for amino acid glutamine

what happens with the repeating codon multiple times in Huntington’s disease

results in mutated protein (mHTT), with a long polyglutamine component - repeated at minimum of 36 times, up to 120 times

how many times does the codon repeat in unaffected individuals

only a dozen times

how many repeats guarantees pathology?

if repeated above 39

normal gene containing

10-26 CAG repeats

Huntington’s Disease gene containing

35 or more CAG repeats

how many people have Huntington’s Disease mutation

approximately 1 in 10,000 individuals - slightly higher in European populations

average diagnosis age

if diagnosed from symptoms rather than genetic screen, age 40

post Huntington’s diagnosis

people usually live an additional 15-20 years but quality of life declines from time of diagnosis

how is damaged caused in Huntington’s

Huntington proteins accumulate through aggregation of hydrogen bonds between peptides, becoming an indigestible mass inside nucleic of certain cells of basal ganglia; brain develops these protein aggregates beginning from BG and eventually affecting many or most cerebrum and cerebellum

what happens with these protein aggregates

thought to inhibit proper functioning of the cells (neurons) leading to death

major symptom of HD

dysregulated motor function, causing movement disturbances

later stages of HD

dystonia (difficulty swallowing), irritability and aggression

clinical signs of HD

cognitive dysfunction - memory and executive dysfunction, psychiatric disturbances -preclinically may exhibit depression, mania, delusions, other psychiatric disorders at considerably higher levels than avg populations, sleep and other mood disorders

visual motor symptoms of HD

chorea, dystonia, motor impersistence, lack of fine motor movement, gait disturbances

chorea

unpredictable and involuntary muscle movements

dystonia

also unpredictable movements but are repetitive and or twisting motions - combined together look rhythmic like combination of fidgeting and dancingg

motor impersistence

cannot maintain voluntary action

gait disturbances

typically slower, more variable lengths of stride, uncoordinated

what does the regular functioning hutingtin gene do?

unclear - potentially role in proper neuronal functioning; conditional knockouts of the protein can highly disrupt brain function; mice without these gene do not survive - critical for neuro-development

what is the connection between Huntington’s disease and nucleic acids?

it is an autosomal dominant mutation in a very specific section of the genome; main cause of disease is genetics

is there the possibility of treating this disease?

because of its specificity, maybe in the future

two major types of nucleic acids

DNA and RNA

how are DNA and RNA different

1. the sugar that attaches to the phosphate backbone or base - deoxyribose or ribose: the lack of oxygen on deoxyribose makes DNA more stable and better able to adhere to complementary strand 2. difference in pyrimidine base - no thymine in RNA, no uracil in DNA

what type of polymers are DNA and RNA

Heteropolymers because they are made of a chain of monomers (nucleotides) that are not all identical

purines

two cyclic chains, slightly larger molecules: adenine (forms two hydrogen bonds with T or U), guanine (forms three hydrogen bonds with C)

pyrimidines

one cyclic chain: cytosine (forms three hydrogen bonds with G), thymine (forms two hydrogen bonds with A), uracil (forms two hydrogen bonds with A)

what pyrimidine are we learning about

5-methylcytosine - thought to play role in DNA transcription regulation /epigenetics

nucleobase

aka base - purine (A or G) or pyrimidine base (C,T or U) = base pairs when they join

nucleoside

the base plus sugar, no matter if deoxyribose or ribose

nucleotide

whole package without bonding between phosphates (phosphodiester linkages) - phosphate, base and sugar combined

primary structure

1. polynucleotides (DNA and RNA) have a sense of direction 2. each of the nucleosides are different

how do polynucleotides have a sense of direction

one side of the chain is the 5’ end which has phosphate attach to the 5-carbon, one side is the 3’ end = this has profound effects on how the strand is read by transcription proteins

which direction does the strand read transcription proteins

generally in the 5 to 3 direction

how are each of the nucleotides different

it is heteromeric, consisting of many different bases

secondary structure

how the molecule is arranged in 3D space - molecule has a defined structure in three dimensions; each turn of the molecule rotates 36 degrees - enough to complete circle in 10 base pairs

symmetry in secondary structure

distance between each of the first carbons in A-T and G-C pairings is exactly the same, angle between each base pairing is 36 degrees, explaining why each helix turn constitutes exactly 10 base pairs