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Section I: 
Cellular and Molecular Neurobiology

15. Genetics and Neuronal Disease
Part 3 of 3

Andrew Bean, Ph.D.

Single Gene or Polygenic?

How can it be determined whether a disease results from mutations in a single gene or multiple genes (polygenic)?  Likely single gene diseases are those in which a single biochemical step is altered (e.g., some lipid storage disorders in which the inactivity of an enzyme leads to the accumulation of a precursor).  Highly complex disorders (e.g., schizophrenia) are likely to be polygenic because of the wide-ranging disease phenotype.

Mapping Complex Traits

Most traits are complex (non-Mendelian). Therefore, in order to attempt to identify genes, two successful strategies have been employed:

  • Define a subtype that shows near-Mendelian inheritance
 
Alzheimer's Disease (AD)

Individuals have been identified who possess early- or late-onset AD phenotype. The early-onset phenotype exhibits near-Mendelian patterns of inheritance. Three genes and one locus were isolated: Amyloid precursor protein (APP), Presenilin-1 (PS-1), Presenilin-2 (PS-2), and apolipoprotein E (ApoE). APP and PS-1 were isolated from early-onset linkage studies while ApoE was from late-onset studies. PS-2 was identified from an ethnic isolate.

 
  • Study families found in an isolated population where the disease incidence is high (many recombination events)
 
Huntington's Disease

Huntington's disease follows an autosomal dominant pattern of inheritance.  However, isolation of the gene underlying this disease was only possible by examining an isolated family in the Lake Maracaibo region of Venezuela.  This family has 12,000 individuals, 258 have the disease, 1227 have 50% risk, 2885 have 25% risk and all are descendents from one woman who lived in the early 1800s.  Linkage mapping enabled the localization of a single gene, the Huntington gene, that codes for the huntingtin protein.  Mutations in the gene result in expanded triplet (CAG) repeats with the number of CAGs proportional to severity of symptoms which are motor and cognitive.

Figure 15.5
 Disorders affecting midbrain dopamine neurons include Parkinson's disease and Huntington's disease. Huntington's disease is a single gene disease resulting from a mutation in the gene coding for huntingtin.  In Huntington's disease, a population of neurons in the striatum degenerate presumably due to the presence of a mutated huntingtin protein.  The mechanism by which this mutated protein produces cell death is being intensely studied but is not yet clear.  The symptoms of Parkinson's disease result from the degeneration of midbrain dopamine neurons in the substantia nigra and ventral tegmental area that project to the striatum and nucleus accumbens.  A candidate gene has been isolated but does not account for the entire phenotype. 

Gene Therapy

Understanding that a particular gene underlies a phenotype is the first step in trying to provide therapeutic benefits to patients carrying a mutation.  However, there are considerable obstacles to overcome between finding the gene and being able to "fix" the mutation.  The strategy employed to functionally "fix" mutations leading to inactive or partially active proteins involves supplying the "correct" gene to the cells needing to produce the inactive protein.   
 
Figure 15.6
Figure 15.7
Figures 15.6 and 15.7. The general strategy involved in "fixing" a mutant gene. 

The major problem is how to get the corrected gene into the appropriate cells.  In many cases a defective viral vector is used that enables entry into cells but lacks the ability to self replicate (Figure 15.6).  A minigene is constructed that contains the "correct" coding region of the wild type protein along with additional sequences necessary for its propogation.  The minigene is packaged and modified cells are made that contain viral particles that make the corrected protein.  These cells are then injected into the patient. Intracranial injection (Figure 15.7) can be used along with various delivery methods (e.g., viral vectors, liposomes) to enable targetting to neural tissues.  Other injection sites can be used for appropriate tissue targetting.

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