Summary
The term autophagy derives from the Greek word autóphagos, which means “self-eating” or “self-digestion.” Autophagy is a fundamental and highly conserved intracellular pathway that in its most basic sense involves the delivery of cytoplasmic cargo to the lysosome for degradation. The Nobel Laureate in Physiology and Medicine in 1974, Christian de Duve, introduced this term to describe the self-eating function of lysosomes in degrading intracellular debris, including damaged organelles (mitochondria, endoplasmic reticulum membranes, ribosomes), and other cellular components such as larger protein aggregates (Harnett et al. 2017). Based on different modes of cargo delivery to lysosomes, three subtypes of autophagy have been defined: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy. In macro-autophagy, cargo is transported inside double-membrane vesicles (or autophagosomes) which are delivered to and fused with lysosomes to form the autolysosome. In micro-autophagy, the cytosolic cargo is trapped in small vesicles formed by invagination of the lysosomal membrane. In chaperone-mediated autophagy, substrates are selectively targeted by hsp70 to the microvesicles and delivered by the receptor protein LAMP2 for lysosomal degradation.
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References
Akizu N, Cantagrel V, Zaki MS, et al. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nat Genet. 2015;47:528–34.
Baulac S, Lenk GM, Dufresnois B, et al. Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology. 2014;82:1068–75.
Beck-Wödl S, Harzer K, Sturm M, et al. Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease—a new type of neuronal ceroid lipofuscinosis (CLN15)? Acta Neuropathol Commun. 2018;6:145.
Bhoj EJ, Li D, Harr M, et al. Mutations in TBCK, encoding TBC1-domain-containing kinase, Lead to a recognizable syndrome of intellectual disability and Hypotonia. Am J Hum Genet. 2016;98:782–8.
Bitoun M, Maugenre S, Jeannet, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 2005;37:1207–9.
Bucelli RC, Arhzaouy K, Pestronk A, et al. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology. 2015;85:665–74.
Byrne S, Jansen L, U-King-Im JM, et al. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain. 2016;139:765–81.
Campeau PM, Lenk GM, Lu JT, et al. Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am J Hum Genet. 2013;92:781–91.
Cullup T, Kho AL, Dionisi-Vici C, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet. 2013;45:83–7.
Dworzak F, Mora M, Borroni C, et al. Generalized lysosomal storage in Yunis Varón syndrome. Neuromuscul Disord. 1995;5:423–8.
Ebrahimi-Fakhari D, Behne R, Davies AK, et al. AP-4-associated hereditary spastic paraplegia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2018. 1993-2020. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/.
Eymard-Pierre E, Lesca G, Dollet S, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002;71:518–27.
Fassio A, Falace A, Esposito A, Aprile D, Guerrini R, Benfenati F. Emerging role of the autophagy/lysosomal degradative pathway in neurodevelopmental disorders with epilepsy. Front Cell Neurosci. 2020;14:39.
Ferreira CR, Rahman S, Keller M, Zschocke J, ICIMD Advisory Group. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. 2021;44:164–77.
García-Cazorla À, Saudubray JM. Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology. J Inherit Metab Dis. 2018;41:1043–54.
Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018;20:233–42.
Haack TB, Hogarth P, Kruer MC, et al. Exome sequencing reveals de novo WDR45 mutations causing phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet. 2012;91:1144–9.
Haack TB, Ignatius E, Calvo-Garrido J, et al. Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. Am J Hum Genet. 2016;99:735–43.
Harnett MM, Pineda MA, Latré de Laté P, et al. From Christian de Duve to Yoshinori Ohsumi: more to autophagy than just dining at home. Biom J. 2017;40:9–22.
Hirst J, Edgar JR, Esteves T, et al. Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet. 2015;24:4984–96.
Kim M, Sandford E, Gatica D, et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. elife. 2016;5:e12245.
Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.
Konno T, Ross OA, Teive HAG, Sławek J, Dickson DW, Wszolek ZK. DCTN1-related neurodegeneration: Perry syndrome and beyond. Parkinsonism Relat Disord. 2017;41:14–24.
Laurin N, Brown JP, Morissette J, Raymond V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002;70:1582–8.
Lenk GM, Szymanska K, Debska-Vielhaber G, et al. Biallelic mutations of VAC14 in pediatric-onset neurological disease. Am J Hum Genet. 2016;99:188–94.
Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.
Lines MA, Ito Y, Kernohan KD, et al. Yunis-Varón syndrome caused by biallelic VAC14 mutations. Eur J Hum Genet. 2017;25:1049–54.
Luciani A, Schumann A, Berquez M, et al. Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. Nat Commun. 2020;11:970.
Maiuri MC, Kroemer G. Therapeutic modulation of autophagy: which disease comes first? Cell Death Differ. 2019;26:680–9.
Montecchiani C, Pedace L, Lo Giudice T, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-tooth disease. Brain. 2016;139:73–85.
Morel E, Mehrpour M, Botti J, et al. Autophagy: a druggable process. Annu Rev Pharmacol Toxicol. 2017;57:375–98.
Nguyen DKH, Thombre R, Wang J. Autophagy as a common pathway in amyotrophic lateral sclerosis. Neurosci Lett. 2019;697:34–48.
Nicholson G, Lenk GM, Reddel SW, et al. Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4. Brain. 2011;134:1959–71.
Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591–8.
Oz-Levi D, Ben-Zeev B, Ruzzo EK, et al. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet. 2012;91:1065–72.
Piano Mortari E, Folgiero V, Marcellini V, et al. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity. Autophagy. 2018;14:22–37.
Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control Centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14:283–96.
Skibinski G, Parkinson NJ, Brown JM, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005;37:806–8.
Soria LR, Brunetti-Pierri N. Ammonia and autophagy: an emerging relationship with implications for disorders with hyperammonemia. J Inherit Metab Dis. 2019;42:1097–104.
Stamatakou E, Wróbel L, Hill SM, et al. Mendelian neurodegenerative disease genes involved in autophagy. Cell Discov. 2020;6:24.
Strømme P, Månsson JE, Scott H, Skullerud K, Hovig T. Encephaloneuropathy with lysosomal zebra bodies and GM2 ganglioside storage. Pediatr Neurol. 1997;16:141–4.
Teinert J, Behne R, Wimmer M, Ebrahimi-Fakhari D. Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy. J Inherit Metab Dis. 2020;43:51–62.
Tosch V, Rohde HM, Tronchere H, et al. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum Mol Genet. 2006;15:3098–106.
Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–60.
Vantaggiato C, Panzeri E, Castelli M, et al. ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. Autophagy. 2019;15:34–57.
Verhoeven K, De Jonghe P, Coen K, et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-tooth type 2B neuropathy. Am J Hum Genet. 2003;72:722–7.
Yang YP, Hu LF, Zheng HF, et al. Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol Sin. 2013;34:625–35.
Zatyka M, Sarkar S, Barrett T. Autophagy in rare (nonlysosomal) neurodegenerative diseases. J Mol Biol. 2020;432:2735–53.
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Dionisi Vici, C., Jungbluth, H., Carsetti, R., van Karnebeek, C.D.M. (2022). Disorders of Autophagy. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_59
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