Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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11 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 DISCUSSING ANT1 ROLE IN AMYOTROPHIC LATERAL SCLEROSIS PATHOGENESIS Dear Editor: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a rapid progression, affecting motor neurons in the brain and spinal cord, ultimately leading to respiratory failure and death. 1 ALS might present as sporadic (sALS) or familial (fALS), both of which are clinically indistinguishable. 1 ALS etiology is still unknown, despite several studies evaluating the underlying mechanism of motor neuron degeneration (e.g., neuroinflammation, oxidative stress, mitochondrial dysfunction, axonal damage, and protein aggregation). 1 Among such mechanisms, mitochondrial dysfunction has been linked to glutamate excitotoxicity, which leads to Ca2+ accumulation in mitochondria, thus resulting in toxic, free radical production. 2 In fact, mitochondria are the energy of cells, and having a central role in cerebral homeostasis. 3 However, mitochondria are sensitive to free radical damage and the resulting dysfunction that is enhanced by glutamate-mediated excitotoxicity. 3 A possible protective role for mitochondria dysfunction might be represented by the adenine nucleotide translocator protein 1 (ANT1), which is the most abundant protein in the inner mitochondrial membrane, with a predominant expression in the heart, brain, and skeletal muscles. 4,5 ANT1 consists of two subunits: ATP synthesis in the mitochondrial matrix and production of ADP from ATP consumption in the cell rest state. Such ATP/ADP exchange induced by ANT1 is essential to maintain the ATP synthase activity and the normal levels of mitochondrial transmembrane potential. 6 Once ATP/ ADP translocate activity is impaired, ANT1 promotes apoptosis. 7 ANT1 has been reported to be involved in several inflammatory diseases of the peripheral nervous system (e.g., sporadic inclusion body myositis 8 ), confirming the interaction between ANT1 and NF-kB, a transcription factor that regulates immune inflammatory responses. 9 Specifically, ANT1, when down regulated, leads to increased concentration of NF-kB in cytosol and promotes anti-apoptotic mechanisms. 8 However, it has been reported that ANT1 alone is the essence of mitochondrial apoptosis and the final target of pro- and anti-apoptotic molecules. 7 Specifically, Martin et al 10 found localization of the core components of the mitochondrial permeability transition pore (mPTP) in ALS mice, suggesting that mitochondria have causal roles in the disease ALS mechanisms. Thus, considering that ANT1 is mainly expressed in the brain, muscle, and heart, even in humans, it is possible that such inflammatory mechanisms in both skeletal muscles and motor neuron disorders (e.g., ALS) exist, supporting a possible mitochondrial dysfunction even in such diseases. Therefore, the interaction between ANT1 and NF-kB in ALS should be better investigated, as this could be an additional factor that promotes oxidative stress, and a possible therapeutic target. References 1. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171. 2. Saba L, Viscomi MT, Caioli S, et al. Altered functionality, morphology, and vesicular glutamate transporter expression of cortical motor neurons from a presymptomatic mouse model of amyotrophic lateral sclerosis. Cereb Cortex. 2016;26(4):1512–28. 3. Bowling AC, Beal MF. Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci. 1995;56:1151–1171. 4. Fagiolari G, Sciacco M, Chiveri L, et al. Lack of apoptosis in patients with progressive external ophthalmoplegia and mutated adenine nucleotide translocator-1 gene. Muscle Nerve. 2002;26:265– 269. 5. Esposito LA, Melov S, Panov A, et al. Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci USA. 1999; 96(9):4820– 4825. 6. Vander Heiden MG, Chandel NS, Schumacker PT, et al. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell. 1999; 3:159–167. 7. Zamora M, Meroño C, Viñas O, et al. Recruitment of NF-kappaB into mitochondria is involved in adenine nucleotide translocase 1 (ANT1)-induced apoptosis. J Biol Chem. 2004;279:38415–38423. 8. Barca E, Aguennouz M, Mazzeo A, et al. ANT1 is reduced in sporadic inclusion body myositis. Neurol Sci. 2013;34(2):217–24. 9. Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001;15:2321–2342. 10. Martin LJ, Gertz B, Pan Y, et al. The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp Neurol. 2009;218(2):333–46. With regard, Simona Portaro, MD, PhD; Vincenzo Cimino, MD, PhD; Antonino Naro, MD, PhD; and Rocco Salvatore Calabrò, MD, PhD All with the IRCCS Centro Neurolesi "Bonino Pulejo" in Messina, Italy. Correspondence: Rocco Salvatore Calabrò, MD, PhD; Email: Funding/financial disclosures: No funding was provided for the preparation of this letter. The authors have conflicts of interest related to the content of this letter. OLANZAPINE AND DIABETIC KETOACIDOSIS: WHAT IS THE UNDERLYING MECHANISM? Dear Editor: Recently, Iwaku et al 1 reported a detailed case of olanzapine-related acute-onset Type 1 diabetes with ketoacidosis. 1 They concluded that olanzapine sometimes can cause sudden hyperglycemia that results in precipitating the onset of Type 1 diabetes. In fact, there is no report of olanzapine-induced diabetes with immunological mechanism. We reported a sporadic case of olanzapine-induced rapid-onset Type 2 diabetes with severe hyperglycemia. 2 In our case, the patient was negative for anti-glutamic acid decarboxylase antibodies, and the discontinuation of olanzapine and careful insulin replacement regimen reversed diabetes. A common feature between these two cases is acute-onset severe hyperglycemia. The first presentation Letters to the Editor Innov Clin Neurosci. 2018;15(3–4):11–14

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