2006 NAF awarded grants.

Your research contributions are used to fund important studies that result in a better understanding of the ataxias. Some scientists are looking for additional genes, while others study identified mutated genes to understand the process by which they cause ataxia. With this understanding they can move on to develop a treatment. The following are summaries of work that you supported for 2006. We look forward to publishing the results when they become available at a later date.

Ilya Bezprozvanny, PhD

University of Texas Southwestern Medical Center in Dallas

Deranged calcium signaling in SCA 3 neurons

Summary: Spinocerebellar ataxia type 3 (SCA3) a fatal neurodegenerative disorder

SCA3 is caused by mutation in protein ataxin-3. We discovered that mutated ataxin-3 binds to and activates the type 1 inositol (1, 4, 5) trisphosphate receptor (InsP3R1) neuronal intracellular calcium (Ca2+) release channel. In this grant I propose experiments with SCA3 mouse model aimed to determine the importance of InsP3R 1 association with mutanted ataxin-3 for SCA3 pathology.

Michael D. Herbert, PhD

The University of Mississippi Medical Center 

PolyQ proteins an d pre-mRNA splicing

Summary: Studies of nuclear organization and function have revealed that the nucleus contains a myriad of dynamic, highly organized domains, territories and bodies. Various diseases are characterized by the disruption of these structures or alteration in their protein composition.

For example, most patients with the neurodegenerative disorder Spinal Muscular Atrophy have a mutation that prevents a crucial protein from localizing to a specific nuclear domain called the Cajal body (CB). In the group of polyglutamine (polyQ) neurodegenerative diseases, the mutant proteins form distinctive nuclear inclusions that may affect the function of the CB.

Current evidence implicates the CB as the site for the maturation of factors necessary for proper RNA processing. The mutant proteins that cause spinocerebellar ataxia 1 or Huntington's disease do not form nuclear inclusions which dramatically alter CB localization. In contrast, mutant ataxin-3 (which causes Machado-Joseph disease) forms inclusions that tether CBs.

We therefore hypothesize that diseases which disrupt the functional organization of the nucleus adversely affect the maturation of factors required for KNA processing. The experiments proposed in this application should greatly clarify our understanding into how polyQ diseases affect the functional organization of the nucleus.

These studies will also provide a rationale for exploring if patient samples have reduced premRNA splicing. With such knowledge, we will be able to ascertain if alterations in RNA processing account for neuronal demise in both polyQ disorders as well as other neurodegenerative diseases such as Spinal Muscular Atrophy. Consequently, therapies designed to increase splicing may be beneficial to patients that suffer from these insidious diseases.

Pawel Kermer, MD

University of Goettingen

Function of the multifunctional protein BAG1 in SCA-3 pathology

Summary: Worldwide, SCA affects some 0.9-3/100,000 individuals, of which SCA-3 is the most common dominantly inherited ataxia. Treatment of the disease is still symptomatic.

Today, neuronal degeneration in the basal ganglia, the brain stem and the cerebellum leading to physical/mental disability and death within years can not be prevented or stopped. Thus, we are in great need for therapeutic strategies aiming at blocking continuous pathology in SCA.

In the present proposal, we suggest experiments involving the neuroprotective protein BAG1, which has been characterized as multifunctional protein linking cell cycle, cell death and stress responses. With its neuroprotective activity being linked to increased levels and foldase activity of Hsp70, BAG1 is a highly interesting gene to study in the context of SCA-3 pathology.

Identification of BAG1 as neuroprotectant in SCA as well as identifying the potential underlying mechanisms could have clinical implications, since the three-dimensional structure of the BAG1/Hsp70-ATPase domain complex has been solved, and critical contact sites have been mapped for BAG1 binding and cochaperone activity.

Thus, it is conceivable that small-molecule drugs could be identified or synthesized for neuroprotection that occupy the BAG1-binding site on the ATPase domain of Hsp70/Hsc70, acting as BAG1 mimics, and thereby enhancing Hsp70/Hsc70 function.

Arnulf H. Koeppen, MD

VA Medical Center

The pathogenesis of hereditary ataxia

Summary: Cerebellar ataxia is the aggregate result of disturbed connections between the cerebellum, the brain stem, and the spinal cord. One group of fiber connections constitutes the "cerebellar module." The participating nerve fibers form a precise triangle between the lower brain stem where the important inferior olive is located, and the Purkinje cells of the cerebellar cortex.

In turn, Purkinje cells send their impulses to a gray matter structure in the depth of the cerebellum, the dentate nucleus. This nucleus is the main way station for information that exits the cerebellum and streams towards the forebrain. However, the dentate nucleus must also report back to the inferior olivary nucleus. The triangular module is continuously active during movement. It provides surveillance and control, and a disturbance in the module causes ataxia.

In most spinocerebellar ataxias (SCA), sporadic ataxia, and Friedreich's ataxia (FRDA), at least one component of the cerebellar module is destroyed. In SCA-1, SCA-2, SCA-7, and the most common form of sporadic ataxia, multiple system atrophy (MSA), an additional problem exists in the gray matter of the pons. The pons, literally the bridge, is a bulging part of the middle brain stem. It conveys abundant impulses to the cerebellum. When its nerve cells degenerate, the patient will have olivopontocerebellar atrophy (OPCA). In SCA3/Machado-Joseph disease (MJD) and FRDA, the disease predominantly affects the dentate nucleus.

The principal investigator seeks to apply his experience with numerous tissue samples from patients with ataxia to an advanced study of the disturbed cerebellar module. The focus is on connections between nerve cells. When a nerve cell dies, it can no longer receive or issue signals. It can also not provide the normal nutrients that travel up and down nerve connections. However, in SCA-6, deprived nerve fibers can seek new connections with neighboring cells and find nutrients from an alternate source.

The investigator also believes that nerve cell loss in the dentate nucleus is due to an inappropriate proliferation of terminals. This phenomenon is especially prominent in the dentate nucleus of patients with SCA- 3/MJD and FRDA. If this research shows that abnormal nerve terminals proliferate and utilize an excess of an otherwise normal transmitter substance, such as glutamic acid, currently available drugs may be beneficial.

Parvoneh Poorkaj Navas, BS, PhD

University of Washington

Genomie mouse models of spinocerebellar ataxia

Summary: Dr. Parvoneh Poorkaj Navas of the University of Washington will develop genetically altered mice that will carry a mutated protein kinase C gamma (PKC gamma) gene. Mutations in PKC gamma are responsible for SCA14, a disease in humans that is characterized by progressive incoordination of gait, often associated with poor coordination of hands, speech and eye movements.

Dr Navas' goal is to study the pathogenesis of cerebellar dysfunction and neurodegeneration throughout the life cycle to aid in the development of treatments for SCA14 and related diseases.

Punett Opal, MD, PhD

Northwestern University

Understanding Spinocerebellar Ataxia Type 1

Summary: Spinocerebellar ataxia type 1 (SCA1) is an inherited disease that causes progressive instability of gait or ataxia. Unfortunately there is no treatment for this relentless disease and those afflicted succumb to complications of cerebellar and brainstem dysfunction. This disease is caused by an expansion of a stretch of glutamines (glutamine is an amino acid) in the disease causing protein, ataxin-1.

Using SCA1 as a model system, our long-term goal is to shed light on two questions pertaining to ataxias: 1) What is the basis for degeneration in cerebellar neurons, the neurons responsible for the co-ordination of movements, and 2) What are the subcellular pathways involved in toxicity? This study addresses both of these issues in SCA 1 by focusing on an ataxin-1 interactor, the Leucine-Rich Acidic Nuclear Protein (LANP).

Based on our preliminary results, we hypothesize that LANP plays a role in SCA1 pathogenesis by serving as a mediator of toxicity in SCA1. Indeed, we have some tantalizing preliminary evidence that reducing LANP levels might prove ameliorative in SCA1 pathogenesis. This grant probes the neuronal functions of LANP with the final aim of delineating its role in SCA1 pathogenesis. We believe that our experiments will help us not only to understand this disease, but also provide clues to treat this otherwise incurable disease.

Susan L. Perlman, MD

David Geffen School of Medicine at UCLA 

Web Access of the National Ataxia Database and a Pilot Epidemiologic Study

Summary: The Cooperative Ataxia Group (CAG), a consortium of 38 North American clinical investigators, have developed a standard database for the ataxic disorders, to be used for a) studies of how specific genes affect cerebellar function and cause disease, b) the identification of new causes of ataxia (genetic and non-genetic), and c) the design of treatment trials for different types of ataxia.

This database has already been computerized and will now be made accessible on the web, for direct use by all ataxia investigators.

Stefan M. Pulst, MD

Cedars-Sinai Medical Center 

Mutation Analysis of the KCNC3 Voltage Gated Potassium Channel in Sporadic and Familial Ataxias

Finding new ataxia genes is still important even if a dozen have already been identified. First and foremost, any new ataxia allows expanded genetic counseling. Equally as importantly, new ataxia genes tell us something about function and dysfunction of the cerebellum.

We have identified the gene for SCA13. Quite surprisingly, SCA13 gene turned out to be a potassium channel. These had not before been considered as being involved in neurodegeneration when mutated.

Laura P.W. Ranura, PhD

University of Minnesota 

Molecular Genetic Characterization of the spinocerebellar ataxia type 5 (SCA5)

Summary: We recently identified the SCA5 gene and currently have a manuscript under review that indicates that the SCA5 mutations affect a protein that is highly expressed in the cerebellum. SCA5 is a slowly progressive disease that usually does not shorten lifespan.

Clinical, neuroimaging and pathological data indicate that SCA5 primarily affects the cerebellum with little or no brainstem involvement, at least for adult-onset cases. Although onset typically occurs in mid-life, a broad range in the age of onset has been observed (10-68 years).

The identification of the SCA5 gene provides a more comprehensive understanding of biochemical changes leading to this group of diseases and to the interdependence of the neuronal systems affected during SCA pathogenesis.

Chin-Cheng Tsai, PhD

UMDNJ-Robert Wood Johnson Medical School

Mechanisms of ataxin-1 mediated cytotoxicity

Summary: My research focuses on ataxin-1, whose glutamine-repeat expanded form causes SCA 1. Although researchers have long thought that insoluble ataxin-1 aggregates are the main culprits for bringing about SCA 1 symptoms, this view has recently been challenged by findings that the detrimental effects of ataxin-1 begin appearing before protein aggregates form, or even when aggregates do not form at all. These observations were made in mice or in fruit flies (Drosophila) that were genetically engineered to express mutant ataxin-1. Such evidence has led many researchers to look once again for what makes mutant ataxin-1 so toxic to certain cells.

We recently found that ataxin-1 binds an important nuclear protein called SMRT (Silencing Mediator or Retinoid and Thyroid hormone receptors) in vertebrate cells; it also binds to a SMRT-related factor, called SMRTER, in flies. Because the main property of SMRT and SMRTER is to help other proteins, such as thyroid hormone receptor in vertebrates or ecdysone receptor in flies, to shut down the transcription of their target genes, the physical interaction we observed between ataxin-1 and SMRT/SMRTER leads us to hypothesize that mutant ataxin-1 may damage cells because of its ability to perturb nuclear receptor signaling pathways.

Because ataxin-1 can interact with SMRTER, and because Drosophila nuclear receptors, like their vertebrate counterparts, use similar methods to regulate gene expression, we propose to use fly as a model system for investigating the relationships among ataxin-1, SMRTER, and nuclear hormone receptors in living organisms. If our studies in flies show promising results, it would help us to design better parallel experiments in vertebrate cells and in live vertebrate animals (where research is much more time-consuming) to see whether the cytotoxicity caused by mutant ataxin-1 is indeed due to disrupted nuclear receptor signaling. Many of these nuclear receptors bind steroid, thyroid, of retinoid hormones; if their properties are indeed affected by mutant ataxin-1, it is possible that drugs that affect the operation of these nuclear receptors could be used to counteract the damaging effects brought about by SCA1.

George R. WIlmot, MD, PhD

Emory University

Cooperative Ataxia Registry

Summary: This registry is designed for patients with ataxia. Ataxia is a group of rare disorders that affect movement and coordination. Because these disorders are rare, it will require a collaborative effort between scientist across North America and patients across North America to complete sound research.

This registry will serve in matching patients interested in participating in research projects with researchers looking for eligible subjects to enroll in their studies. After signing an informed consent form and an authorization to obtain medical records form, potential subjects will complete a patient information form and mail them or fax them to the registry office. After review of the data, eligibility will be determined by the principal investigator. The data will be entered by hand and stored in a secure database on a computer.

The registry will support two different types of subsequent studies. First, patient data that is stripped of all identifying information can be accessed directly by researchers who have submitted qualifying study protocols to the registry. Second, ataxia researchers can submit research protocols requiring identifying information, and if a protocol is approved by the registry principal investigator, potentially eligible patients will be mailed information on the study. The information sheet will provide a brief description of the study and a phone number to contact the study coordinator. It will be up to the patient to determine if they are interested in calling to get more information about the study. At no time will patient contact information be provided to the researcher by the registry.

One purpose of the study is to collect data and personal contact information, on an ongoing basis, about patients diagnosed with ataxia. This identifiable data will enable us to contact patients to provide information on research studies available. Another purpose will be to use this data to study the natural history of these disorders and will allow identification of the features which may be most sensitive to change, and/or interventions that may be tested in collaborative studies in the future. Patients enrolled in the registry will have the opportunity to enroll in future treatment protocols, if they are eligible and so desire, but will sign a different, specific, consent form for those studies at that time. After the information listed above is obtained, it will be submitted to the cooperative registry. Patients can refuse any part of the data collection they do not wish to participate in.

This research may help us to learn more about this group of rare diseases and may help to form a basis for future treatment protocols that have not been available to date.

Young Investigator Award 2005-06

Armin Alaedini, PhD

Weill Medical College of Cornell University

Immune reactivity to synapsin in the ataxia associated with gluten sensitivity

Summary: Celiac disease is a complex autoimmune disease that is triggered by ingestion of gluten in genetically susceptible individuals. It is a common disease (prevalence of 1% in United States and Europe), which is associated with multiple extra intestinal manifestations.

Cerebellar ataxia is among the most common and debilitating neurologic complications associated with gluten sensitivity. The associated ataxia has been suspected to have an autoimmune component, with gliadin playing a central role in the pathogenic mechanism. In preliminary studies, we have found that antibodies to gliadin cross-react with and bind to a major protein of the nervous system, called synapsin 1. The synapsin 1 protein has a key role in the release of neurotransmitters in the nervous system. Our hypothesis is that such cross-reactivity of anti-gliadin antibodies against the synapsin 1 molecule plays a pathogenic role and is associated with neurologic manifestations, including cerebellar ataxia.

We propose to test this hypothesis as follows: 1) To determine whether there is an association between anti-gliadin antibody cross-reactivity with synapsin 1 and presence of gluten sensitivity in ataxia patients, 2) To map the cross-reactive amino acid sequences of the synapsin 1 molecule, and 3) To determine whether the cross-reactive antibodies exhibit pathogenic characteristics that have potential for causing disease.

The proposed studies are expected to shed light on how cerebellar ataxia may be associated with gluten sensitivity. They may also serve to provide a useful antibody marker for the diagnosis of gluten sensitivity-associated cerebellar ataxia, and offer a rationale for examining the efficacy of therapies that target autoimmune mechanisms in affected patients.

Research Fellowship Award

Kerri Carlson, PhD

University of Minnesota

Tools for SCA 1 Therapeutics

Summary: Spinocerebellar ataxia-1 type 1 (SCA 1) is a neurodegenerative, genetic disorder caused by a mutation in the SCA 1 gene. The SCA 1 gene codes for the ataxin-1 protein.

Recent studies using a mouse model suggest that therapies aimed at reducing the levels of the ataxin-1 protein in cells may be effective for treating SCA1. The phosphorylation of serine 776 in the ataxin-1 protein has been linked to the stability of-the ataxin-1 protein in the cell and has been demonstrated to be necessary for disease to occur. We propose that strategies aimed at preventing this phosphorylation event from occurring may be lead candidates for SCA 1 treatments.

The aim of this proposal is to identify both chemical and genetic factors that regulate ataxin-1 S776 phosphorylation. First, we have screened a library of small molecules to identify chemical modulators of S776 phosphorylation. We will perform follow up studies on lead chemicals that were identified as hits in our primary screen. In these studies we will study the specificity of each compound for ataxin-1 phosphorylation as well as examine both their cytotoxicity and determine the effective dose of each compound.

Next, we will use a secondary screen to validate compounds that we determine are highly specific inhibitors of ataxin-1 S776 phosphorylation with minimal cytotoxicity. This secondary screen will be performed using a cerebellar slice culture system. In this system thin slices of the cerebellum from a SCA 1 mouse will be exposed to our lead candidate compounds and maintained for varying amounts of time. We will then assess whether our candidate compounds continue to affect ataxin-1 S776 phosphorylation in our slice cultures. Using a cerebellar slice culture system will allow us to validate multiple hits in an environment that more closely resembles the mammalian cerebellum. Compounds that are validated using our cerebellar slice culture system will become lead compounds to follow up on in I experiments using animal models.

The second part of this proposal is aimed at identifying the specific proteins (called kinases) that are involved in phosphorylating ataxin-1 S776. To accomplish this aim, we will use a technique called siRNA to decrease the expression of different kinases in the cell and then monitor the levels of ataxin-1 S776 phosphorylation. Through these experiments we will identify kinases that specifically regulate ataxin-1 S776 phosphorylation. The identification of these kinases will help us to better understand SCA1 pathology. In addition, these kinases will also become novel targets for the development of a SCA 1 therapeutic.

Irene De Biase, MD, PhD

Board of Regents of the University of Oklahoma Health Sciences Center

Somatic instability in the pathogenesis and treatment of Friedreich ataxia

Summary: Friedreich ataxia is the most common inherited ataxia. It is caused when patients inherit large expansions of a GM triplet-repeat mutation from either parent. Whereas everyone who inherits these mutations develops disease, patients show a remarkable degree of variability in clinical manifestations. Even though the size of the GM triplet-repeat mutation generally determines the severity of disease, frequently individuals with the same size of repeat show very different clinical severities. Moreover, individuals who inherit mutations are usually asymptomatic until their teenage years, at which time the disease initiates, and then progresses relentlessly. Another confounding feature is that some regions of the nervous system degenerate early in the disease process compared with other regions, and some regions remain normal throughout.

The causes of the individual variability despite inheriting similar mutations, the progressive nature of disease, and the selective damage to specific regions of the nervous system remain unknown. We believe that the reason stems from the behavior of the GM triplet-repeat mutation in specific tissues and its alteration during the aging of patients.

We have found promising preliminary evidence to support our hypothesis and would like to comprehensively address this issue by analyzing the behavior of this mutation in various tissues derived from autopsies of 10 individuals who died of Friedreich 1 ataxia. Our ultimate goal is to develop strategies to alter the behavior of this repeat sequence, slowing or preventing further expansion, in patient cells as a potential mechanism to slow the progression of disease. We propose to test various chemotherapeutic drugs in patient cells cultured in the lab in order to test their effect on altering the behavior of the GM triplet-repeat I mutation.

We believe that our studies will help to better understand why the disease is progressive, and perhaps yield clues to the development of strategies to slow the progression of disease.

Gumei Liu, PhD

University of Iowa 

Disease-regulated RNA interference for Spinal Ataxia Type 1 therapy

Summary: Spinal cerebellar ataxia remains a fatal, dominant neurogenetic disease. While supportive therapies exist, the development of an effective treatment is warranted. We previously showed that attacking the fundamental problem of mutant gene expression could be one approach to therapy. To accomplish this, we used a method called ANA interference, or RNAi. RNAi refers to a process whereby target genes are inhibited from being expressed. We showed, using a mouse model of SCA 1, that reducing disease gene expression improved the motor incoordination and improved the pathology in the cerebellum, the major site of disease in this model.

In our prior work, we accomplished RNAi using a system that would have it 'on' at all times. We do not know if such a system is needed or sale for a disease that can span decades. For this reason, I propose to develop an RNAi system that turns on when the cells are sick, and off when the cells recover. We know the cells can recover to some extent because of other mouse work done by Dr. Harry Orr, U of Minn.

How to accomplish this? I propose that this can be done using inhibitory RNA which are naturally expressed in brain cells. While we don't know what these naturally occurring RNAi are doing, we do know that some of them are expressed at higher levels in SCA 1 mice brains. We will use the elements that make them be expressed upon disease onset, and off in healthier brains, to drive RNAi specific for mutant ataxin-1. This system would take advantage of the cells natural ability to turn things on and off as needed, and represents a very novel approach to SCA1 therapy.

Greg Mayeur, PhD

University of California, Davis 

Late Onset Ataxia Due to a CGG Repeat Expansion in the FMR1 Gene

Summary: Fragile X-associated Tremor/ Ataxia Syndrome (FXTAS) is a recently discovered ataxia associated with Fragile X Syndrome (FXS). Both FXTAS and FXS result from an expansion of the CGG repeats located in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR 1). FXTAS occurs in older patients classified as premutation for CGG repeat number (55-200 repeats), whereas FXS is found in childhood patients with greater than 200 repeats (full mutation). Despite being caused by the same gene, FXTAS and FXS are caused by entirely distinct molecular mechanisms. While FXS is a protein deficiency disorder caused by gene silencing, FXTAS is caused by elevated expression of expanded repeat mRNA, not lowered levels of the FMR1 protein (FMRP).

FXTAS appears to affect primarily older (>50 years) male carriers of premutation alleles, although some female carriers are also affected. The major clinical features of FXTAS include gait ataxia, and progressive intention tremor, with Parkinsonism, and peripheral neuropathy being more variable symptoms. Gait ataxia begins with balance problems, particularly with tandem gait. Walking difficulties progress to the point where successive use of cane, walker, and wheelchair is required. Based on results of ataxia/tremor screening of adult premutation carriers, and a premutation carrier frequency of 1:800 for males in the general population, an estimated 1:3000 males poses a risk of developing FXTAS over their lifetime. Additionally screens of ataxia populations have identified 2-5% as carriers of the premutation alleles.

Based on the current observations we hypothesize that FXTAS is likely caused by a RNA "toxic I gain-of-function." The four main arguments that support this are: 1) The ataxia is exclusively: confined to carriers of the premutation. 2) The dysregulation of transcription in the premutation: range. 3) A CGG repeat model of FXTAS upstream of a heterogous reporter in Drosophila melanogaster exhibits similar neuropathology. 4) The FMR1 mRNA is found in intranuclear inclusions found in FXT AS patients.

To examine this hypothesis we propose two specific aims: 1) To identify trans-acting factors that interact directly with the FMR 1 CGG repeat, and the potential neurpathologies of this interaction and 2) Identify the transcriptional regulatory factors that lead to elevated FMR1 mRNA levels.

Sokal V. Todi, PhD

The University of Iowa

Generating a conditional knockout mouse to investigate the functional necessity of MJD1, the causative gene for Spinocerebellar Ataxia 3, in mammals

Spinocerebellar Ataxia 3 (SCA3), also known as Machado-Joseph Disease (MJD), is the most common dominantly inherited ataxia. SCA3/MJD arises from the expansion of a region of the protein ataxin-3 from 12-41 to over 60 repeats of the amino acid glutamate. SCA3/MJD affects nervous system areas such as the basal ganglia, brainstem, cerebellum, and the spinal cord.

Not much is known about ataxin-3 functions in an organism. Studies conducted thus far have only shed light onto ataxin-3 interactions with other proteins and some of its enzymatic properties. As a matter of fact, we do not even know if ataxin-3 is an essential protein in mammals.

Research indicates that a considerable number of genes in our genome are not functionally necessary. In this proposal, we will investigate if MJD1, the gene which produces ataxin-3, is necessary for proper functioning of mammals. We aim to generate a mouse model where MJD1 is removed from the animal's genome, to understand functional necessities of ataxin-3 in otherwise normal animals.

The information gathered will be important in answering crucial questions, such as: Is ataxin-3 functionally necessary during development or in the adult mammal?; What are some possible functions it plays in the nervous system and other organ systems?; Can therapeutic techniques, which will properly combat deleterious effects of SCA3/MJD, be successfully designed and safely implemented?

Natascia Venture, MD, PhD

University of Rome "Tor Vergata"

Experimental Medicine and Biochemical Science

Summary: This project is intended to provide insight into the molecular pathogenesis of Friedreich's Ataxia (FRDA), the most common inherited ataxia. FRDA is caused by the defective expression of the I FXN (FRDA, X25) gene, which leads to impaired expression of the encoded protein, frataxin.

We recently generated a new powerful genetic tool to gain insight into the molecular pathogenesis of Friedreich's Ataxia (1). Lowering C.elegans frataxin homologue by RNAi, unexpectedly, increases nematode life span. In C.elegans, neverthteless, this is consistent with inactivation or reduction of other proteins involved in mitochondrial metabolism.

Worms with low level of frataxin are smaller, paler, have lower brood size and affected sensitivity to oxidative stress compare to control RNAi red worm. Since most of the pathways so far described in C.elegans are very well conserved in humans, our provocative finding suggest new appealing function for frataxin in pathways controlling cell growth, metabolism, aging and the stress response. Different hypotheses can be formulated with the purpose of uncovering a role for frataxin in these important biological processes. In the nematode C. elegans, mutations that impact on life span belong mostly to the dauer-specifying insulin/IGF-1-like pathway and to proteins affecting mitochondrial metabolism. In both cases though, increased longevity can be ascribed to alterations in energy metabolic pathways, eventually resulting in increased resistance to stress.

Understanding how C.elegans copes, and actually lives longer, with decreased frataxin could then shed lights on specific signal transduction pathways regulated frataxin.

We propose a model in which lowering frataxin affect mitochondrial metabolism and increase free radicals production within a certain level that early in life may still induce stress response pathways and alter specific genes to maintain energy metabolism and rescue cell viability. Once beyond the threshold, free radical may induce an oxidative damage no longer tolerated from cells, which will eventually degenerate. The early induction of protective pathways would account and be sufficient to prolong C.elegans life-span. More importantly, the same pathways, activated early in life in FRDA cells, will rescue cell degeneration if supported with specific therapy before cell physiology is completely dismantled.

The general aim of this project is then to shed light on premature signal transduction pathways affected by frataxin deficiency, which might be difficult to be recognized once the pathology is established. This will suggest new specific therapeutic strategies to prevent the diseases progression.