The Neurochemistry of fr iedreich’s Ataxia

1. The Neurochemistry of friedreich’sAtaxia PHM 142 Andrea Lam Bingqing Li Jessica Ragazzo Annie Xiao PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is Friedreich’s Ataxia? • FA, FRDA • Rare recessively inherited neurodegenerative disease, does not affect cognitive abilities (Hereditary ataxia) • 1863 (NikolausFriedreich) • Genetic defect in FXN gene • http://en.wikipedia.org/wiki/Nikolaus_Friedreich

3. Ataxia • Hereditary ataxia: poor coordination of hands, speech, legs (unsteady gait, loss of feeling) Results from one or more of: • Cerebellum dysfunction • Spinal cord lesions • Sensory loss (Peripheral) Adapted from (Bird 1998) • bthsbioteacher.wikispaces.com

4. Statistics • Most common form of inherited ataxia (but rare) • 3-4 cases per 100 000 Caucasians • 1-2 cases per 40 000 Canadians • Significant healthcare costs

5. Signs and Symptoms • Typical age of onset: puberty; Late onset: after 25 • “Degenerative atrophy of the posterior columns of the spinal cord” – Dr. Friedreich • Ataxia: gait instability, loss of balance, difficulty in activities • Dysarthria: slow and jerky speech unintelligible • Limb weakness: proximal muscles disability

6. Signs and Symptoms • Sensory neuropathy (DRG) • Loss of sensory fibres • Degeneration of spinal cord • Decreased perceptions • Cardiomyopathy (secondary) • Diabetes (10%) • Carbohydrate intolerance (20%)

7. Genetics of Friedreich’s Ataxia • Autosomal recessive disease involving the FXN gene on chromosome 9 • FXN codes for a mitochondrial protein known as frataxin • Normal allele – “GAA” is repeated 7-22 times • Mutant allele – “GAA” is repeated hundreds to thousands of times • This “triplet repeat extension” blocks transcription of the FXN gene • Individuals with the disease have low levels of frataxin, but it is not completely absent – this would result in lethality in the embryonic stage of development

8. Roles of Frataxin in Mitochondria • Reducing oxidative stress: • The Fenton reaction (Fe2+ + H2O2 +H+ → Fe3+ + HO• + H2O) causes oxidative stress • Frataxin protects against the formation of free radicals • Iron chaperone: • Heme biosynthesis – frataxin delivers iron to ferrochelatase for insertion into porphyrin rings • Iron-sulfur cluster synthesis – low frataxin levels results in diminished iron-sulfur cluster levels which are needed in proteins involved in mitochondrial electron transport, thus energy production is reduced

9. Pathogenesis • Iron overload leads to: • Free radical production • Oxidative stress • Result in damages to: • CNS/PNS • Heart • Pancreas

10. Pathology • Neurological damages occur mainly in: • Dentate Nuclei (DN) of cerebellum • Involved in proprioception & coordination • Damage leads to ataxia & dysarthria • Dorsal Root Ganglia (DRG) and dorsal roots • Contains afferent sensory neurons • Damage leads to compromised sensory perception • Corticospinal tracts • Is a descending motor pathway • Damage leads to muscular atrophy

11. Pathology • Heart damages result in: • Cardiomyopathy • Hypertrophy of heart leads to heart failure • Pancreatic damages result in: • Diabetes Mellitus • Elevated blood sugar • Result from destruction of pancreatic β-cells due to excess ROS and apoptosis

12. Diagnostic Tests • Electromyogram (EMG) • MRI, CT • Electrocardiogram (ECG) • Blood tests (Glucose) • Genetic Test (PCR, Southern blots)

13. Summary • Rare recessively inherited neurodegenerative disease (hereditary ataxia, most common) • Hereditary Ataxia: poor coordination resulting from  cerebellum dysfunction, spinal cord lesions, sensory loss (peripheral) • Tests: EMG, ECG, blood (glucose), genetic • Signs and symptoms: ataxia, dysarthria, limb weakness and sensory neuropathy • Autosomal recessive disease involving the FXN gene which codes for frataxin, a mitochondrial protein • Frataxin is deficient, but not completely absent, in individuals with Friedreich’s ataxia • Frataxin reduces oxidative stress by protecting against the Fenton reaction • Frataxin is an iron chaperone involved in heme biosynthesis and iron-sulfur clusters • ROS production and oxidative stress leads to pathologies in nervous system (dentate nuclei, dorsal root ganglia and dorsal roots, corticospinal tract), heart, and pancreas, leading to sensory and motor disabilities, cardiomyopathy, and diabetes mellitus

14. References • Beinert, H. et al. 1997. Iron-Sulfur Clusters: Nature’s Modular, Multipurpose Structures. Science. 277(5326): 653-659. • Bird, T.D. 1998. Hereditary Ataxia Overview. GeneReviews™ [Internet]. Seattle: University of Washington. Retrieved 31 Oct 2013. < http://www.ncbi.nlm.nih.gov/books/NBK1138/>. • Brendel B. et al. 2013. Friedreich ataxia: dysarthria profile and clinical data. Cerebellum. 12: 475-484. • Canadian Association for Familial Ataxias. Friedreich’s Ataxia (FA) Facts. Retrieved 31 Oct 2013. < http://thewalktofightfa.com/documents/Friedreich%20english.pdf>. • Campuzano, V et al. 1996. Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion. Science. 271(5254): 1423-1427. • Cotticelli MG et al. 2013. Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids. Redox Bio. 1: 398-404. • Friedreich’s Ataxia Research Alliance. About FARA: What is Friedreich’s Ataxia?. Retrieved 21 Oct 2013. < http://www.curefa.org/whatis.html>. • "Friedreich's Ataxia Fact Sheet," NINDS. Publication date September 2010. • Koeppen, A.H. 2011. Friedreich’s ataxia: Pathology, pathogenesis, and molecular genetics. J Neurol Sci. 303, 1-2. • Muscular Dystrophy Canada. 2007. Friedreich’s Ataxia (FA). Retrieved 31 Oct 2013. < http://www.muscle.ca/fileadmin/National/Muscular_Dystrophy/Disorders/427E_Friedreichs_Ataxia_2007.pdf>. • Muthuswamy, S., Agarwal, S., Dalal, A.R. 2013. Diagnosis and Genetic Counseling for Friedreich’s Ataxia: A time for consideration of TP-PCR in an Indian Setup. Hippolratia. 17(1): 38-41. • National Institute of Neurological Disorders and Stroke. 2011. Friedreich's Ataxia Fact Sheet. Retrieved 31 Oct 2013. < http://www.ninds.nih.gov/disorders/friedreichs_ataxia/detail_friedreichs_ataxia.htm#174163070>. • Pandolfo, M. 1999. Molecular Pathogenesis of Friedreich Ataxia. Arch. Neurol. 56: 1201-1208.   • Parkinson, M.H., Boesch, S., Nachbauer, W., Mariotti, C. and Giunti, P. 2013. Clinical features of Friedreich's ataxia: classical and atypical phenotypes. J. Neurochem. 126: 103-117. • Polek, B., Roach, M.J., Andrews, W.T., Ehling, M., Salek, S. 2013. Burden of Friedreich’s Ataxia to the Patients and Healthcare Systems in the United States and Canada. Front Pharmacol. 4: 1-7. doi:  10.3389/fphar.2013.00066. < http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660667/>. • Puccio, H. and Koenig M. 2000. Recent advances in the molecular pathogenesis of Friedreich ataxia. Human Mol. Gen. 9(6): 887-892. • Schulz J. B., Boesch S., Bürk K., Dürr A., Giunti P., Mariotti C., Pousset, F., Schols, L., Vankan P., Pandolfo, M. 2009. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat. Rev. Neurol. 5: 222–234. < http://www.nature.com/nrneurol/journal/v5/n4/full/nrneurol.2009.26.html>. •  Schulz, J.B., Pandolfo, M. 2013. 150 years of Friedreich Ataxia: from its discovery to therapy. J. Neurochem. 126: 1-3. < http://onlinelibrary.wiley.com/doi/10.1111/jnc.12327/pdf>. • Soderberg, C.A.G. et al. 2013. The Molecular Basis of Iron-induced Oligomerization of Frataxin and the Role of the Ferroxidation Reaction in Oligomerization. Biol Chem. 288(12): 8156-8167.