Nucleic Acids Overview

Lecture Overview

  • Topic: Nucleic Acids (Chapter 4)
  • Focus Areas:
    • Huntington’s Disease as an example of an autosomal dominant mutation.
    • Review of DNA and RNA
    • Purines and pyrimidines in DNA and RNA
    • Primary and secondary structure of DNA and RNA
    • Historical context of DNA's ability to transfer information, focusing on key papers.

Huntington’s Disease

  • Nature of the Disease:
    • Autosomal dominant disorder caused by mutation in the huntingtin (HTT) gene.
    • Characterized by the repetition of the CAG codon (codes for glutamine) ranging from 36 to 120 times.
  • Genetic Repetition:
    • Normal individuals: 10-26 CAG repeats; Disease: >39 repeats leads to nearly guaranteed pathology.
  • Pathological Protein:
    • Mutated protein (mHTT) results from excessive CAG repeats, leading to a long polyglutamine tail.

Etiology and Epidemiology

  • Prevalence:
    • Occurs in approximately 1 in 10,000 individuals; slightly higher in European populations.
    • Mostly inherited; only 0.1% of cases are spontaneous mutations.
  • Age of Diagnosis:
    • Average age of symptom onset is around 40 years; prognosis of 15-20 years post-diagnosis with declining quality of life.

Pathology

  • Mechanism of Cell Damage:
    • Unclear, but aggregation of mutated huntingtin proteins causes cellular damage.
    • Protein aggregates form indigestible mass in the nucleus of basal ganglia cells, disrupting neuron function and leading to cell death.
  • Impact on Brain Regions:
    • Initially affects basal ganglia; eventually impacts the cerebrum and cerebellum.

Clinical Signs and Symptoms

  • Motor Dysfunction:
    • Chorea: involuntary muscle movements.
    • Dystonia: repetitive twisting movements.
    • Motor impersistence: inability to maintain voluntary actions (e.g., holding out tongue).
  • Cognitive and Psychiatric Symptoms:
    • Memory dysfunction, executive dysfunction.
    • Higher incidence of depression, mania, delusions before diagnosis; aggression and mood disorders in later stages.

Function of Normal Huntingtin Gene

  • Current Understanding:
    • The exact function remains largely unknown.
    • Potential role in neuronal function; deletion in animal models leads to severe dysfunction.

Huntington's Disease and Nucleic Acids

  • Genetic Basis:
    • Specific mutation in the HTT gene, emphasizing impact of genetics on health.
  • Research Opportunities:
    • Future treatment prospects involving CRISPR/Cas9 gene editing technology as a potential intervention.
    • Reference: "CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease" (Yang et al., 2017).

Nucleic Acids: Overview

  • Types of Nucleic Acids:
    • DNA (Deoxyribonucleic Acid)
    • RNA (Ribonucleic Acid)
  • Key Differences:
    1. Sugar Types: DNA contains deoxyribose, which lacks an oxygen atom, making it more stable than ribose in RNA.
    2. Base Composition: DNA contains thymine whereas RNA contains uracil.

Primary Structure of Nucleic Acids

  • Directionality:
    • Polynucleotides have a clear 5' to 3' direction, influencing transcription and function.
  • Heteromeric Composition:
    • Each nucleic acid strand contains various nucleosides (A, T, G, C in DNA; A, U, G, C in RNA).

Experiments Establishing Genetic Material Nature

  1. Avery et al. (1944): Established that nucleic acids can induce transformation in bacteria.
  2. Hershey and Chase (1952): Differentiated between nucleic acids and proteins as carriers of genetic information using radioactive labeling.

Secondary Structure of Nucleic Acids

  • Helical Structure:
    • DNA forms a double helix with specific distances and angles between base pairs, critical for stability and function.
    • Each complete turn of the DNA helix corresponds to 10 base pairs and is 36 degrees of rotation.

Upcoming Topics

  • Tertiary structure of DNA/RNA.
  • DNA denaturation and replication processes.
  • Transcription and translation mechanisms.