Treating Spinocerebellar Ataxias with Antibiotics: a Promising Approach from Preclinical Models

Project location: ITALY, Pozzuoli
Project start date: April 2017 - Project end date: September 2018
Project number: 2017-033
Beneficiary: Fondazione Telethon

Spinocerebellar ataxia (SCA), also known as spinocerebellar atrophy or spinocerebellar degeneration, is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right.

SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

TIGEM developed a detailed characterization of the molecular events leading to spinocerebellar ataxia type 28 (SCA28), a rare form of cerebellar degeneration (Maltecca et al., 2008, Maltecca et al., 2009, Maltecca et al., 2012). This knowledge allowed TIGEM  to formulate a possible treatment of the preclinical SCA28 model with ceftriaxone (CEF), a known antibiotic, which revealed to be extremely effective in preventing or ameliorating the ataxic symptoms (Maltecca et al., 2015). Based to a strong rationale, this project proposes to test the same pharmacological approach with CEF on other forms of SCA, such as SCA1 and SCA2, which represent approximately 50% of all autosomal dominant forms of spinocerebellar ataxia.

SCA28 is a novel form of juvenile onset spinocerebellar ataxia caused by mutations of the AFG3L2 gene characterized by unbalanced standing, gait incoordination, nystagmus, ophthalmoparesis and pyramidal signs (Di Bella et al., 2010). AFG3L2 coassembles with paraplegin into multimeric complexes, called the m-AAA proteases, in the inner mitochondrial membrane (Koppen and Langer, 2007). We demonstrated that the haploinsufficient Afg3l2+/- mouse recapitulates the features of SCA28 patients (Maltecca et al., 2009). The SCA28 mouse displays motor incoordination due to dark cell degeneration (DCD) and loss of Purkinje cells (PCs). DCD of PCs in the SCA28 mouse is quite particular since it originates from mitochondrial dysfunction, while in other forms of SCA it is associated to a dysfunctional glutamatergic system. We demonstrated that the triggering event of PC-DCD in SCA28 mice is a defective calcium internalization in mitochondria, which in turn causes alteration of calcium homeostasis under normal glutamate stimulation, thus mimicking excitotoxic-mediated DCD.
We provide the first evidence of a pre-clinical treatment of this disease by leveraging on a peculiar side activity of beta-lactam antibiotics that are able to increase the expression of the glutamate transporter GLT1/EAAT2 in astrocytes (Rothstein et al., 2005). This enhanced GLT1 expression provokes the reduced glutamate stimulation of PCs and, therefore, protects Purkinje cells from calcium-excess degeneration, thus rescuing the clinical and neuropathological signs of ataxia (Maltecca et al., 2015).
Both SCA1 and SCA2 could benefit from CEF treatment. In fact, it has been reported that the ataxic phenotype of SCA1 is dramatically exacerbated in the absence of calbindin-D28K, a calcium buffering protein essential for PC survival (Vig et al., 2012), while SCA2 mutant protein, the expanded ataxin-2, binds to the intracellular calcium release channel IP3R1 and increases the release of calcium upon IP3 stimulation (Liu et al., 2009).
TIGEM recently obtained the Orphan Drug Designation from European Medicine Agency for CEF treatment of spinocerebellar ataxia (

Cited References
Di Bella, D., Lazzaro, F., Brusco, A., Plumari, M., Battaglia, G., Pastore, A., Finardi, A., Cagnoli, C., Tempia, F., Frontali, M., Veneziano, L., Sacco, T., Boda, E., Brussino, A., Bonn, F., Castellotti, B., Baratta, S., Mariotti, C., Gellera, C., Fracasso, V., Magri, S., Langer, T., Plevani, P., Di Donato, S., Muzi-Falconi, M. & Taroni, F. 2010. Mutations In The Mitochondrial Protease Gene Afg3l2 Cause Dominant Hereditary Ataxia Sca28. Nature Genetics, 42, 313-21.
Koppen, M. & Langer, T. 2007. Protein Degradation Within Mitochondria: Versatile Activities Of Aaa Proteases And Other Peptidases. Crit Rev Biochem Mol Biol, 42, 221-42.
Liu, J., Tang, T. S., Tu, H., Nelson, O., Herndon, E., Huynh, D. P., Pulst, S. M. & Bezprozvanny, I. 2009. Deranged Calcium Signaling And Neurodegeneration In Spinocerebellar Ataxia Type 2. J Neurosci, 29, 9148-62.
Maltecca, F., Aghaie, A., Schroeder, D. G., Cassina, L., Taylor, B. A., Phillips, S. J., Malaguti, M., Previtali, S., Guenet, J. L., Quattrini, A., Cox, G. A. & Casari, G. 2008. The Mitochondrial Protease Afg3l2 Is Essential For Axonal Development. J Neurosci, 28, 2827-36.
Maltecca, F., Baseggio, E., Consolato, F., Mazza, D., Podini, P., Young, S. M., Jr., Drago, I., Bahr, B. A., Puliti, A., Codazzi, F., Quattrini, A. & Casari, G. 2015. Purkinje Neuron Ca2+ Influx Reduction Rescues Ataxia In Sca28 Model. The Journal Of Clinical Investigation, 125, 263-74.
Maltecca, F., De Stefani, D., Cassina, L., Consolato, F., Wasilewski, M., Scorrano, L., Rizzuto, R. & Casari, G. 2012. Respiratory Dysfunction By Afg3l2 Deficiency Causes Decreased Mitochondrial Calcium Uptake Via Organellar Network Fragmentation. Hum Mol Genet, 21, 3858-70.
Maltecca, F., Magnoni, R., Cerri, F., Cox, G. A., Quattrini, A. & Casari, G. 2009. Haploinsufficiency Of Afg3l2, The Gene Responsible For Spinocerebellar Ataxia Type 28, Causes Mitochondria-Mediated Purkinje Cell Dark Degeneration. J Neurosci, 29, 9244-54.
Rothstein, J. D., Patel, S., Regan, M. R., Haenggeli, C., Huang, Y. H., Bergles, D. E., Jin, L., Dykes Hoberg, M., Vidensky, S., Chung, D. S., Toan, S. V., Bruijn, L. I., Su, Z. Z., Gupta, P. & Fisher, P. B. 2005. Beta-Lactam Antibiotics Offer Neuroprotection By Increasing Glutamate Transporter Expression. Nature, 433, 73-7.
Vig, P. J., Wei, J., Shao, Q., Lopez, M. E., Halperin, R. & Gerber, J. 2012. Suppression Of Calbindin-D28k Expression Exacerbates Sca1 Phenotype In A Disease Mouse Model. Cerebellum, 11, 718-32.

This project, which received a grant from the Nando and Elsa Peretti Foundation, aims at demonstrating the efficacy of CEF on SCA2, a form of SCA much more frequent than SCA28, already known to benefit from the treatment. This will open to additional forms of SCA, such as SCA5 and SCA7, which involve the increase of cytoplasmic calcium as the triggering event of degeneration. While SCA28 is quite rare among autosomal dominant spinocerebellar ataxias (3% in Italy and UK), SCA2 patients represent the 25% in Europe, 24% in Italy and 40% in UK. An effective treatment for SCA28 and SCA2 is therefore of high impact.

TIGEM already obtained the Orphan Drug Designation for the treatment of ataxia with CEF. This project is pivotal to the set-up of the human protocol for SCA28 and SCA2 patients that could be started in following next year.

More specifically, the expected outcomes will be pivotal to human clinical trial and include information on:

• CEF is effective on the SCA2 model.
• defining the correct design of human patient treatment..
• identifying peripheral markers to monitor EAAT2/GLT1 expression in glial cells.

The Telethon Institute of Genetics and Medicine is located in Pozzuoli (Naples, Italy) in an over 4000 square meter facility. The Institute counts with 19 Faculty Members and >200 people including graduate students, post-docs, technical and administrative staff. Research at TIGEM focuses on the study, prevention and cure of human genetic diseases. It is supported by several core facilities ( dedicated to providing state-of-the-art technology as well as housekeeping assistance. All the facilities present at TIGEM will be completely available for this project. 

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