Abstract
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscle wasting and lacks an effective treatment. ALS pathogenesis has not been elucidated yet. In a small proportion of ALS patients, the disease has a familial origin, related to mutations in specific genes, which directly result in MN degeneration. By contrast, the vast majority of cases are though to be sporadic, in which genes and environment interact leading to disease in genetically predisposed individuals. Lately, the role of the environment has gained relevance in this field and an extensive list of environmental conditions have been postulated to be involved in ALS. Among them, infectious agents, particularly viruses, have been suggested to play an important role in the pathogenesis of the disease. These agents could act by interacting with some crucial pathways in MN degeneration, such as gene processing, oxidative stress or neuroinflammation. In this article, we will review the main studies about the involvement of microorganisms in ALS, subsequently discussing their potential pathogenic effect and integrating them as another piece in the puzzle of ALS pathogenesis.
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References
Zufiria M, Gil-Bea FJ, Fernandez-Torron R, Poza JJ, Munoz-Blanco JL, Rojas-Garcia R et al (2016) ALS: a bucket of genes, environment, metabolism and unknown ingredients. Prog Neurobiol 142:104–129
Riancho J, Lozano-Cuesta P, Santurtun A, Sanchez-Juan P, Lopez-Vega JM, Berciano J et al (2016) Amyotrophic lateral sclerosis in northern Spain 40 years later: what has changed? Neurodegener Dis 16(5–6):337–341
Hardiman O, van den Berg LH, Kiernan MC (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol 7(11):639–649
Riancho J, Berciano MT, Ruiz-Soto M, Berciano J, Landreth G, Lafarga M (2016) Retinoids and motor neuron disease: potential role in amyotrophic lateral sclerosis. J Neurol Sci 360:115–120
Al Chalabi A, Hardiman O, Kiernan MC, Chio A, Rix-Brooks B, van den Berg LH (2016) Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 15(11):1182–1194
Riancho J, Gonzalo I, Ruiz-Soto M, Berciano J (2016) Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis. Neurologia. https://doi.org/10.1016/j.nrl.2015.12.001
Al Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9(11):617–628
Riancho J, Bosque-Varela P, Perez-Pereda S, Povedano M, de Munain AL, Santurtun A (2018) The increasing importance of environmental conditions in amyotrophic lateral sclerosis. Int J Biometeorol. https://doi.org/10.1007/s00484-018-1550-2
Karim S, Mirza Z, Kamal MA, Abuzenadah AM, Azhar EI, Al Qahtani MH et al (2014) The role of viruses in neurodegenerative and neurobehavioral diseases. CNS Neurol Disord Drug Targets 13(7):1213–1223
Babiker A, Jeudy J, Kligerman S, Khambaty M, Shah A, Bagchi S (2017) Risk of cardiovascular disease due to chronic hepatitis c infection: a review. J Clin Transl Hepatol 5(4):343–362
Limongi D, Baldelli S (2016) Redox imbalance and viral infections in neurodegenerative diseases. Oxid Med Cell Longev 2016:6547248
Araujo AQ (2015) Update on neurological manifestations of HTLV-1 infection. Curr Infect Dis Rep 17(2):459
Zhou L, Miranda-Saksena M, Saksena NK (2013) Viruses and neurodegeneration. Virol J 10:172
Bowen LN, Tyagi R, Li W, Alfahad T, Smith B, Wright M et al (2016) HIV-associated motor neuron disease: HERV-K activation and response to antiretroviral therapy. Neurology 87(17):1756–1762
Rowland LP (2011) HIV-related neuromuscular diseases: nemaline myopathy, amyotrophic lateral sclerosis and bibrachial amyotrophic diplegia. Acta Myol 30(1):29–31
McCormick AL, Brown RH Jr, Cudkowicz ME, Al Chalabi A, Garson JA (2008) Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology 70(4):278–283
Verma A, Berger JR (2006) ALS syndrome in patients with HIV-1 infection. J Neurol Sci 240(1–2):59–64
Bastos AF, Orsini M, Machado D, Mello MP, Nader S, Silva JG et al (2011) Amyotrophic lateral sclerosis: one or multiple causes? Neurol Int 3(1):e4
Louboutin JP, Strayer D (2014) Role of oxidative stress in HIV-1-associated neurocognitive disorder and protection by gene delivery of antioxidant enzymes. Antioxidants (Basel) 3(4):770–797
Regulier EG, Reiss K, Khalili K, Amini S, Zagury JF, Katsikis PD et al (2004) T-cell and neuronal apoptosis in HIV infection: implications for therapeutic intervention. Int Rev Immunol 23(1–2):25–59
Douville RN, Nath A (2017) Human endogenous retrovirus-K and TDP-43 expression bridges ALS and HIV neuropathology. Front Microbiol 8:1986
Westarp ME, Ferrante P, Perron H, Bartmann P, Kornhuber HH (1995) Sporadic ALS/MND: a global neurodegeneration with retroviral involvement? J Neurol Sci 129(Suppl):145–147
Alkhawajah NM, Chapman KM, Moore GR, Oger J (2015) Amyotrophic lateral sclerosis presentation of a human T-lymphotropic virus type-1 myelopathy-insight into pathogenesis. APMIS 123(9):815–820
Dekaban GA, Hudson AJ, Rice GP (1992) Absence of HTLV-I and HTLV-II proviral genome in the brains of patients with multiple sclerosis and amyotrophic lateral sclerosis. Can J Neurol Sci 19(4):458–461
Silva MT, Leite AC, Alamy AH, Chimelli L, Andrada-Serpa MJ, Araujo AQ (2005) ALS syndrome in HTLV-I infection. Neurology 65(8):1332–1333
Brutting C, Emmer A, Kornhuber ME, Staege MS (2017) Cooccurrences of putative endogenous retrovirus-associated diseases. Biomed Res Int 2017:7973165
Brown RH Jr, Al Chalabi A (2015) Endogenous retroviruses in ALS: a reawakening? Sci Transl Med 7(307):307fs40
Douville R, Liu J, Rothstein J, Nath A (2011) Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol 69(1):141–151
Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J et al (2015) Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 7(307):307ra153
Bhat RK, Rudnick W, Antony JM, Maingat F, Ellestad KK, Wheatley BM et al (2014) Human endogenous retrovirus-K(II) envelope induction protects neurons during HIV/AIDS. PLoS One 9(7):e97984
Contreras-Galindo R, Gonzalez M, Almodovar-Camacho S, Gonzalez-Ramirez S, Lorenzo E, Yamamura Y (2006) A new real-time-RT-PCR for quantitation of human endogenous retroviruses type K (HERV-K) RNA load in plasma samples: increased HERV-K RNA titers in HIV-1 patients with HAART non-suppressive regimens. J Virol Methods 136(1–2):51–57
Li W, Li G, Steiner J, Nath A (2009) Role of Tat protein in HIV neuropathogenesis. Neurotox Res 16(3):205–220
Wurdinger T, Gatson NN, Balaj L, Kaur B, Breakefield XO, Pegtel DM (2012) Extracellular vesicles and their convergence with viral pathways. Adv Virol 2012:767694
Ravits J (2005) Sporadic amyotrophic lateral sclerosis: a hypothesis of persistent (non-lytic) enteroviral infection. Amyotroph Lateral Scler Other Motor Neuron Disord 6(2):77–87
Fung G, Shi J, Deng H, Hou J, Wang C, Hong A et al (2015) Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis. Cell Death Differ 22(12):2087–2097
Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P et al (2003) Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. Eur J Epidemiol 18(2):123–127
Finnen RL, Pangka KR, Banfield BW (2012) Herpes simplex virus 2 infection impacts stress granule accumulation. J Virol 86(15):8119–8130
Finnen RL, Hay TJ, Dauber B, Smiley JR, Banfield BW (2014) The herpes simplex virus 2 virion-associated ribonuclease vhs interferes with stress granule formation. J Virol 88(21):12727–12739
Reed D, Plato C, Elizan T, Kurland LT (1966) The amyotrophic lateral sclerosis/parkinsonism-dementia complex: a ten-year follow-up on Guam. I. Epidemiologic studies. Am J Epidemiol 83(1):54–73
TORRES J, IRIARTE LL, Kurland LT (1957) Amyotrophic lateral sclerosis among Guamanians in California. Calif Med 86(6):385–388
Reed DM, Brody JA (1975) Amyotrophic lateral sclerosis and parkinsonism-dementia on Guam, 1945–1972. I. Descriptive epidemiology. Am J Epidemiol 101(4):287–301
Murch SJ, Cox PA, Banack SA (2004) A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci USA 101(33):12228–12231
Murch SJ, Cox PA, Banack SA, Steele JC, Sacks OW (2004) Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand 110(4):267–269
Field NC, Metcalf JS, Caller TA, Banack SA, Cox PA, Stommel EW (2013) Linking beta-methylamino-L-alanine exposure to sporadic amyotrophic lateral sclerosis in Annapolis, MD. Toxicon 70:179–183
Caller TA, Chipman JW, Field NC, Stommel EW (2013) Spatial analysis of amyotrophic lateral sclerosis in Northern New England, USA, 1997–2009. Muscle Nerve 48(2):235–241
Lannuzel A, Mecharles S, Tressieres B, Demoly A, Alhendi R, Hedreville-Tablon MA et al (2015) Clinical varieties and epidemiological aspects of amyotrophic lateral sclerosis in the Caribbean island of Guadeloupe: a new focus of ALS associated with Parkinsonism. Amyotroph Lateral Scler Frontotemporal Degener 16(3–4):216–223
Masseret E, Banack S, Boumediene F, Abadie E, Brient L, Pernet F et al (2013) Dietary BMAA exposure in an amyotrophic lateral sclerosis cluster from southern France. PLoS One 8(12):e83406
Spencer PS, Roy DN, Ludolph A, Hugon J, Dwivedi MP, Schaumburg HH (1986) Lathyrism: evidence for role of the neuroexcitatory aminoacid BOAA. Lancet 2(8515):1066–1067
Lobner D, Piana PM, Salous AK, Peoples RW (2007) Beta-N-methylamino-l-alanine enhances neurotoxicity through multiple mechanisms. Neurobiol Dis 25(2):360–366
Bradley WG, Mash DC (2009) Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. Amyotroph Lateral Scler 10(Suppl 2):7–20
Chernoff N, Hill DJ, Diggs DL, Faison BD, Francis BM, Lang JR et al (2017) A critical review of the postulated role of the non-essential amino acid, beta-N-methylamino-l-alanine, in neurodegenerative disease in humans. J Toxicol Environ Health B Crit Rev 20(4):1–47
Bradley WG (2015) The John Walton Muscular Dystrophy Research Centre in the University of Newcastle and the BMAA theory of motor neuron disease. J Neuromuscul Dis 2(s2):S77–S81
Sieh W, Choi Y, Chapman NH, Craig UK, Steinbart EJ, Rothstein JH et al (2009) Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates. Hum Mol Genet 18(19):3725–3738
Burakgazi AZ (2014) Lyme disease-induced polyradiculopathy mimicking amyotrophic lateral sclerosis. Int J Neurosci 124(11):859–862
Hemmer B, Glocker FX, Kaiser R, Lucking CH, Deuschl G (1997) Generalised motor neuron disease as an unusual manifestation of Borrelia burgdorferi infection. J Neurol Neurosurg Psychiatry 63(2):257–258
Visser AE, Verduyn Lunel FM, Veldink JH, van den Berg LH (2017) No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study. Eur J Neurol 24(1):227–230
Qureshi M, Bedlack RS, Cudkowicz ME (2009) Lyme disease serology in amyotrophic lateral sclerosis. Muscle Nerve 40(4):626–628
Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375(24):2369–2379
Rhee SH, Pothoulakis C, Mayer EA (2009) Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 6(5):306–314
Westfall S, Lomis N, Kahouli I, Dia SY, Singh SP, Prakash S (2017) Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci 74(20):3769–3787
Dobashi Y, Yoshimura H, Atarashi E, Takahashi K, Tohei A, Amao H (2013) Upregulation of superoxide dismutase activity in the intestinal tract mucosa of germ-free mice. J Vet Med Sci 75(1):49–54
Dobashi Y, Itoh K, Tohei A, Amao H (2014) Screening for intestinal microflora influencing superoxide dismutase activity in mouse cecal mucosa. J Vet Med Sci 76(3):453–456
Wu S, Yi J, Zhang YG, Zhou J, Sun J (2015) Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol Rep 3(4):1–10
Zhang YG, Wu S, Yi J, Xia Y, Jin D, Zhou J et al (2017) Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clin Ther 39(2):322–336
Fang X, Wang X, Yang S, Meng F, Wang X, Wei H et al (2016) Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing. Front Microbiol 7:1479
Brenner D, Hiergeist A, Adis C, Mayer B, Gessner A, Ludolph AC et al (2018) The fecal microbiome of ALS patients. Neurobiol Aging 61:132–137
Nicolson GL, Nasralla MY, Haier J, Pomfret J (2002) High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with amyotrophic lateral sclerosis (ALS). J Clin Neurosci 9(5):525–529
Flores-Rio de la Loza LJ, Ordonez-Lozano G, Pineda-Olvera B (2005) Determination of systemic infections due to mycoplasma in patients with clinically defined amyotrophic lateral sclerosis. Rev Neurol 41(5):262–267
Hibbett DS, Taylor JW (2013) Fungal systematics: is a new age of enlightenment at hand? Nat Rev Microbiol 11(2):129–133
Wainwright M (2003) An alternative view of the early history of microbiology. Adv Appl Microbiol 52:333–355
Baxi SN, Portnoy JM, Larenas-Linnemann D, Phipatanakul W (2016) Exposure and health effects of fungi on humans. J Allergy Clin Immunol Pract 4(3):396–404
Pisa D, Alonso R, Carrasco L (2011) Fungal infection in a patient with multiple sclerosis. Eur J Clin Microbiol Infect Dis 30(10):1173–1180
Pisa D, Alonso R, Juarranz A, Rabano A, Carrasco L (2015) Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J Alzheimers Dis 43(2):613–624
Pisa D, Alonso R, Jimenez-Jimenez FJ, Carrasco L (2013) Fungal infection in cerebrospinal fluid from some patients with multiple sclerosis. Eur J Clin Microbiol Infect Dis 32(6):795–801
Alonso R, Pisa D, Marina AI, Morato E, Rabano A, Rodal I et al (2015) Evidence for fungal infection in cerebrospinal fluid and brain tissue from patients with amyotrophic lateral sclerosis. Int J Biol Sci 11(5):546–558
Alonso R, Pisa D, Fernandez-Fernandez AM, Rabano A, Carrasco L (2017) Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis. Neurobiol Dis 108:249–260
Hooten KG, Beers DR, Zhao W, Appel SH (2015) Protective and toxic neuroinflammation in amyotrophic lateral sclerosis. Neurotherapeutics 12(2):364–375
Carvalho A, Cunha C, Pasqualotto AC, Pitzurra L, Denning DW, Romani L (2010) Genetic variability of innate immunity impacts human susceptibility to fungal diseases. Int J Infect Dis 14(6):e460–e468
Harvey WT, Martz D (2007) Motor neuron disease recovery associated with IV ceftriaxone and anti-Babesia therapy. Acta Neurol Scand 115(2):129–131
Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14(4):248–264
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Castanedo-Vazquez, D., Bosque-Varela, P., Sainz-Pelayo, A. et al. Infectious agents and amyotrophic lateral sclerosis: another piece of the puzzle of motor neuron degeneration. J Neurol 266, 27–36 (2019). https://doi.org/10.1007/s00415-018-8919-3
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DOI: https://doi.org/10.1007/s00415-018-8919-3