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Molecular Basis of Some Neurological Disorders Said Ismail Dept. of Biochemistry. Molecular Basis of Neurological Disorders. Neurological Disorders. disorders which involve: - The central nervous system (brain, brainstem and cerebellum)

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Molecular Basis of Some Neurological Disorders

Said Ismail

Dept. of Biochemistry

Molecular Basis of Neurological Disorders

Neurological Disorders

disorders which involve:

- The central nervous system (brain, brainstem and cerebellum)

- The peripheral nervous system (including cranial and peripheral nerves)

Major examples:

Neurodegenerative diseases:

- affecting movement - Parkinson's disease (PD)

- Huntington's disease (HD)

- memory loss and Dementia - Alzheimer


Epilepsy and Seizures



Molecular Basis of Neurological Disorders

Common causes:
  • Inherited genetic abnormalities
  • Problems in the immune system
  • Injury to the brain or nervous system
  • other diseases such as Diabetes

Molecular Basis of Neurological Disorders

WHO numbers: March 2007

Hundreds of million worldwide are affected by neurological disorders:


50 million: epilepsy;

62 million: cerebrovascular disease;

326 million: migraine;

24 million: Alzheimer disease & other dementias

- 6.8 million people die every year as a result of neurological disorders

Molecular Basis of Neurological Disorders

Huntington’s Disease (HD):
  • - Major example of inherited neurological disorders (ND)
  • - Unlike other common NDs:
  • single genetic cause in all patients (ie single disease mechanism)
  • Symptoms:
  • - abnormal body movements called chorea and a lack of coordination
  • - Also involves behavioral and intellectual problems
  • Age of onset:
  • all ages but majority in middle age
  • Death typically occurs 15 years after motor symptoms onset

Molecular Basis of Neurological Disorders

HD Inheritance and Genetics:
  • All cases: due to expansion of the CAG tri-nucleotide repeat in the HD gene
  • HD gene is found on short arm of chromosome 4
  • There are normally: 6 – 34 CAG units (>34 repeats result in HD)
  • In rare HD Heterozygotes, the longer repeat determines the age of onset
  • (the second repeat has no effect):
  • HD is autosomal dominance (at least in regard to age of onset)

Molecular Basis of Neurological Disorders

Inheritance of Huntington disease

Molecular Basis of Neurological Disorders

The extended CAG repeat:
  • CAG repeat: located in coding sequence near 5’ end of HD gene
  • When CAG is > 34: Inheritance is meiotically not stable (specially from father)
  • (Child usually has longer CAG region compared to father (earlier onset)
  • Age of Onset: depend largely on length of CAG repeat
  • (The Longer the CAG repeat the Younger the onset of disease)
  • NO correlation between CAG length and Duration of disease (onset to death)
  • Only Little effect of CAG length on progression of symptoms
  • So, Mechanism of disease onset night be different from mechanism of
  • disease progression

Molecular Basis of Neurological Disorders

Correlation of HD CAG-repeat length with age at onset

Molecular Basis of Neurological Disorders


- CAG repeats: Encodes a poly-Glutamine tract beginning 18 aa of the N-terminus

- HD protein: “Huntingtin” large (> 3,100 aa)

- expressed in both neuronal and non-neuronal tissues

- expression not limited to neurons affected in HD !!

- Expanded CAG repeats and extended polyglutamine tract have been

found in other proteins involved in other inherited neurodegenerative dis.s

Molecular Basis of Neurological Disorders

Toxic effect of HD polyglutamine tract:
  • Still not very clear
  • Only the N-terminus of Huntingtin is necessary for HD symptoms
  • General hypothesis:
    • - HD is a conformational disease in which the pathogenic pathway is triggered
    • In some manner by protein mis-folding and its consequences including
    • Formation of aggregate structures

Molecular Basis of Neurological Disorders

Alzheimer’s disease:
  • Most common cause of Dementia (50-60 %)
  • First described 100 years ago by Alois Alzheimer, Germany.
  • Dementia:
  • - < 1% in people aged 60-64 years
  • - 24 – 33% in people over 85 years
  • - World wide: - 24 million in 2004
  • - 81 million in 2040 (due to increased life expectancy)
  • - Familial and sporadic forms

Molecular Basis of Neurological Disorders

Genetics of Alzheimer’s:
  • “Familial” type:
    • Autosomal dominant disorder with onset before 65 years
    • Rare: prevalence below 0.1%
    • Genes involved:
    • - Presenilin 1 (PSEN1) & Presenilin 2 (PSEN2): most familial cases
    • - Amyloid precursor protein (APP): only few cases

Molecular Basis of Neurological Disorders

“Sporadic” type:

- Almost 80% is linked to genetic factors

- Apolipoprotein E (APOE) ε4 allele: most important predisposing risk factor

- APOE: is a cholesterol transporter in Brain

(APOE4: low efficiency variant in reuse of membrane lipids and repair)

- Hetero APOE ε4: 3 fold increase in risk

- Homo APOE ε4: 15 fold increase in risk

- APOE ε4 allele affects mainly the age of onset:

- each allele copy lower age of onset by 10 years

- NO other gene has been shown to have similar significance

(probably because sporadic form are the result of accumulated small

effects of several genes plus the environmental factors)

Molecular Basis of Neurological Disorders

Genetic Causes of Alzheimer's Disease



Molecular Basis of Neurological Disorders

Parkinson’s Disease (PD):
  • - The second most common adult onset neurological condition
  • Affects over 1% of people over 65 years
  • Main symptoms: bradykinisia, tremor, and rigidity
  • Sporadic PD:
  • - only little gene association has been uncovered so far (5-10%)
      • caused by a combination of environmental toxins acting via inhibition
      • of the mitochondrial respiratory chain to produce dopaminergic cell
      • loss and inclusion bodies leading to increase in oxidative stress.

Molecular Basis of Neurological Disorders

celebrity patients: Michael J. Fox and Muhammad Ali

Molecular Basis of Neurological Disorders

Familial PD:
  • - rare
  • - Some variants are autosomal recessive and some are autosomal dominant
  • Ex1: DJ-1 gene:
  • - causes an autosomal recessive type of PD
  • - Normal DJ-1 appears to provide neuro-protection against
  • oxidative stress caused by mitochondrial toxins
  • (Mutated DJ-1 does not)
  • Ex 2: PINK1 gene:
  • - also causes an autosomal recessive type of PD
      • also have neuroprotective properties against a variety of cellular
      • stresses
      • (mutated forms (eg G309D) lose such properties)
  • Ex 3: parkin and α-synuclein: involved in juvenile and early-onset PD
  • - parkin gene: autosomal dominant
  • - α-synuclein: autosomal recessive

Molecular Basis of Neurological Disorders

Table 1. Summary of the genes accounting for the Mendelian forms of PD and the major published mutations identified in these genes

AD, autosomal dominant; AR, autosomal recessive, Homozygous mutations are only shown for genes causing autosomal recessive PD. Although several heterozygous mutations have been identified in all genes causing autosomal recessive PD, the pathological significance remains unclear.

aThe G2019S mutation in the LRRK2 gene has been reported a number of times and appears to account for 3–7% familial PD and 1–1.6% of so-called ‘sporadic PD’ (57,58,59).

Autosomal dominant inheritance when one parent either has PD or has the faulty

α-synuclein gene copy.

  • 40% of cases are associated with genetic factors
  • Genetic Epilepsies:
  • 1. Mendelian disorders:
  • single major locus account for segregation of disease
  • 2. Non-Mendelian (complex) diseases:
  • several gene loci implicated in addition to environmental factors
  • or by maternal inheritance pattern of mitochondrial DNA
  • 3. Chromosomal disorder:
  • Gross cytogenetic abnormality is present

Molecular Basis of Neurological Disorders

  • Over 200 Mendelian diseases include epilepsy in their phenotype
  • BUT, all are rare (1% of all patients)
  • Channelopathies: arise from mutation in both voltage-gated and ligand-gated ion
  • ion channels
  • complex:
  • Most common familial type of epilepsy
  • Chromosomal:
  • Trisomy 21 (Down Syndrome)
  • Trisomy 12p

Molecular Basis of Neurological Disorders

Neuroscience and Stem cell research:
  • Promising animal model and human experiments
  • Political and ethical debate !!
      • USA: September 2001 restrictions by Bush
  • Example Target Disorders:
  • - Neurodegenerative disorders:
  • Parkinson’s & Huntington’s: localized degeneration: easier cell therapy
  • Alzheimer: affected neurons are less defined
  • - Spinal cord injuries

Molecular Basis of Neurological Disorders

Making the Headlines


published 4/3/2011 in the journal Stem Cells (Kessler and Bissonnette)

Northwestern Medicine researchers for the first time have transformed a human embryonic stem cell into a critical type of neuron that dies early in Alzheimer’s disease and is a major cause of memory loss.

This new ability to reprogram stem cells and grow a limitless supply of the human neurons will enable a rapid wave of drug testing for Alzheimer’s disease, allow researchers to study why the neurons die and could potentially lead to transplanting the new neurons into people with Alzheimer’s.Thesecritical neurons, called basal forebrain cholinergic neurons, help the hippocampus retrieve memories in the brain.

Human Skin Cells Transformed into Stem Cells and then Neurons

In new, unpublished research:

Northwestern Medicine scientists also have discovered a second novel way to make the neurons. They made human embryonic stem cells (called induced pluripotent stem cells) from human skin cells and then transformed these into the neurons.

Scientists made these stem cells and neurons from skin cells of three groups of people: Alzheimer’s patients, healthy patients with no family history of Alzheimer’s, and healthy patients with an increased likelihood of developing the disease due to a family history of Alzheimer’s because of genetic mutations or unknown reasons.


Molecular Basis of Neurological Disorders