PHM142 Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
The Neurochemistry of
Friedreich’s Ataxia
By: Michelle Donnelly, Virginia Gamero, Vinson Li, and Pooja Maharajh
Learning Objectives
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Define Friedreich’s Ataxia
Understand the genetics of Friedreich’s Ataxia
Recognize the gross pathology of the disease
Understand the frataxin molecular mechanism
Be able to list some signs and symptoms and why they are present in the disease
Recognize the incidence of FRDA
What does it mean to have
Friedreich’s Ataxia?
• Ataxia – “Lack of Order”- Greek
• Defined as a loss of full control of body movements.
• Generally the nerves that are affected can be missing from birth.
• One of the most studied rare genetic diseases, and the most common Ataxia.
Source:
http://www.ninds.nih.gov/disord
ers/friedreichs_ataxia/friedreich
s_ataxia.htm
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Friedreich’s Ataxia is A
Genetic
Disorder
We first found out that the Friedreich’s Ataxia gene is on
chromosome 9. The impacted gene is the FXN gene which
transcribes fxn.
Autosomal recessive disease
Intron of FXN usually has a GAA triplet-repeat mutation
Change in methylation pattern immediately upstream of exon 1
Inhibited transcription
Leads to a deficiency in frataxin
Sticky DNA
Stabilized mRNA once transcribed
The protein produced is normal. The problem is making it.
Sources: http://www.fasebj.org/content/22/6/1625.full
What does it mean to have
Friedreich’s Ataxia?
• The frataxin gene is expressed differently in certain tissues
• High expression: liver, muscle, thymus, CNS, heart, pancreas,
liver, skeletal muscle
• Two determinants of pathology in high expression tissues:
• Dividing cells (liver and muscle) versus nondividing cells (CNS, heart,
pancreas) - affects regeneration
• High metabolic requirements (CNS and heart) versus low metabolic
requirements - affects toxicity
Sources: http://www.mda.org/disease/friedreichs-ataxia/overview
http://journals1.scholarsportal.info.myaccess.library.utoronto.ca/pdf/08878994/v28i0005/335_fa.xml
What does it mean to have
Friedreich’s Ataxia?
*Decreased frataxin
decreases NADH
production AND
decreases ISC’s,
therefore increasing
hydroxyl radical
buildup.
Sources: http://www.nature.com/nrn/journal/v5/n8/images/nrn1474-f2.jpg
Decreased Frataxin decreases NaDH production
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Proteins of oxidative
phosphorylation
* Note: Nature has stated they are referring the
hydroxyl radical when they include OH-.
• Frataxin is used to decrease
• ISC = Iron-sulfur complex
• Found in many proteins, especially
those proteins involved in ETC
(Electron transport chain).
• Increases Fe2+ by decreasing Fe3+
and therefore decreasing OH
radicals.
• When Frataxin levels are low in cells
where they are usually expressed
(brain, cerebellum, etc- high
metabolic rate), as in Friedrich’s
ataxia, OH radicals rise, doing
damage to neurons.
Lowering Frataxin levels lowers ISC’s
• Thus, increased iron in the cell causes increased
running of the following pathway.
• IscU Iron-Cluster Assembly Enzyme: Acts as a
scaffold to assemble the cluster of Fe2S2.
• Isu1p and Isu2p create Fe2 from the
Us
elemental iron pumped into the cell.
• IscS = Cysteine desulfurase breaks down
amino acids to attain sulfur and add it to the ISC.
• Nfs1p adds the sulfur from the cysteine
to the Fe2 complex
• Recall: Increased iron is being pumped out of the
cell in increased amounts.
• Positive Feedback
It’s all Connected! 
Us
How common is Friedreich’s Ataxia?
• FRDA frequency is 1:50,000
• Carrier frequency is 1:60 – 1:100
• FRDA occurs in populations from Europe, the Middle East, North Africa, and India and is
absent in populations from East Asia and in Native Americans
• Symptoms typically begin between 5-15 years
• After 10-15 years, patients are usually wheelchair bound
• The average life expectancy is 40-50 years
• Most commonly reported cause of death are cardiac failure and arrhythmias
Signs and Symptoms of
Friedreich’s Ataxia Explained
• Longer nerve tracts are usually most affected.
• In the CNS: the long spinal cord transmits information to the brain and from the brain to
the peripheral nervous system
• Most notably affected: the cerebellum (no energy reserves) atrophies
• Symptoms: difficulty with balance, walking, loss of coordination
• In the PNS: the long peripheral nerve fibers that send information to the muscles and
receive information from the periphery.
• PNS signals fail to reach the muscles
• Symptoms: weakness
• Progression of symptoms: legs, arms, speech, vision, hearing.
Source: http://quest.mda.org/sites/default/files/In_Focus-FA_2011_2.pdf
Summary Slide- Friedreich’s Ataxia
• Rare, but most common ataxia and most
studied rare disease
• Absent from East Asian and American Indian
populations.
• Autosomal recessive disease of FXN gene (GAA
triplet-repeat mutation) on chromosome 9
that transcribes frataxin (fxn).-deficiency in
frataxin via Sticky DNA and stabilized mRNA
• Decreased frataxin decreases NADH and ISC
production- increasing hydroxyl radical
buildup.
• Frataxin helps form ISC’s using Fe. So frataxin
= ISC’s and Fe3+ and ROS.
• ISC’s in proteins involved in ETC, so  frataxin
= NADH.
• Frataxin helps IscU and IscS become Ns1p and isu1p and isu2p that make ISC’s from dietary iron and cysteine amino acids.
• Increased Fe3+ pumped into cell accelerates this, so pathway has positive feedback.
• FXN gene High expression and loss of function: cerebellum (no energy reserves), liver, heart, pancreas, skeletal muscle +
others- where there’s high metabolic rate.
• PNS signals cannot reach the muscles- Longer nerve tracts are more affected due to lack of energy production.
• Lack of regeneration of dividing cells and toxicity to high metabolic rate cells.
• Symptoms: difficulty with balance, walking, loss of coordination, overall weakness. Progression of symptoms: legs, arms,
speech, vision, hearing. but Typically die of cardiac failure or arrhythmias
Additional Sources
http://www.fasebj.org/content/22/6/1625.full
http://painresource.com/nervous-system/peripheral-neuropathies-friedreichs-ataxia/
http://www.nature.com/nrn/journal/v5/n8/full/nrn1474.html
http://quest.mda.org/sites/default/files/In_Focus-FA_2011_2.pdf
http://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm
http://patient.info/doctor/friedreichs-ataxia
http://www.curefa.org/whatis
http://www.ncbi.nlm.nih.gov/books/NBK1281/
http://quest.mda.org/sites/default/files/In_Focus-FA_2011_2.pdf
http://journals1.scholarsportal.info.myaccess.library.utoronto.ca/pdf/08878994/v28i0005/335_fa.xml
http://www.nature.com/nrn/journal/v5/n8/fig_tab/nrn1474_F2.html
https://en.wikipedia.org/wiki/Friedreich%27s_ataxia
https://en.wikipedia.org/wiki/Frataxin
http://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm