Autophagy in Neurons

“The best characterized autophagy receptor known to function in aggrephagy is p62/ SQSTM1 (Bjørkøy et al. 2005, Komatsu et al. 2007a, Pankiv et al. 2007).”

“Work has shown that PINK1 is a mitochondrially-targeted kinase involved in the recruitment of the E3 ubiquitin ligase Parkin to impaired mitochondria (Narendra et al. 2008, 2010a).”

“While many questions remain, the importance of autophagy in neurons is clear, as the neuron-specific ablation of autophagy leads to neurodegeneration (Hara et al. 2006, Komatsu et al. 2006).”

“While many questions remain, the importance of autophagy in neurons is clear, as the neuron-specific ablation of autophagy leads to neurodegeneration (Hara et al. 2006, Komatsu et al. 2006).”

“21(12):1995–2003 [PubMed: 21885617] Haack TBB, Iuso A, Kremer LSS, Hartig M, Strom TMM, et al. 2016 Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.”

“Depletion of a single receptor such as OPTN may induce a delay in mitochondrial engulfment (Moore & Holzbaur 2016) but does not block mitophagy completely (Lazarou et al. 2015), indicating some redundancy in the system.”

“Elongation of the autophagosome membrane is mediated by the aptly named elongation complex, composed of two ubiquitin-like conjugation complexes (Ichimura et al. 2000, Mizushima et al. 1998).”

“Likewise, conditionally knocking out Atg7 in Purkinje cells using the Pcp2 promoter in mice did not appear to affect dendrites, but did lead to neuronal and axonal dystrophy, degeneration of axon terminals, and eventual neuronal death (Komatsu et al. 2007b).”

“Upon stimulation with low-dose NMDA, dendritic spines displayed an increase in GFP-LC3 puncta.”

“ATG9 is thought to shuttle between the membrane source and the growing autophagosome, possibly bringing lipids to the autophagosome.”

“Elongation of the autophagosome membrane is mediated by the aptly named elongation complex, composed of two ubiquitin-like conjugation complexes (Ichimura et al. 2000, Mizushima et al. 1998).”

“…al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport (Nicolas et al. 2018, Wong & Holzbaur 2014b), and autophagosomelysosome fusion or acidification (Lie & Nixon 2018, Nixon et al. 2005) across disease models.”

“When activated, ULK1 phosphorylates other autophagy pathway components, including Beclin1 (BECN1) and ATG9 (Feng et al. 2014, Kamada et al. 2000, Russell et al. 2013, Zhou et al. 2017).”

“Virtually every possible membrane source, including plasma membrane (Hollenbeck 1993; Ravikumar 2010), mitochondria (Hailey et al. 2010), Golgi (van der Vaart et al.”

“The ATG12-ATG5 conjugate, along with ATG16L1, acts as the E3-like enzyme to conjugate mATG8s to phosphatidylethanolamine (PE) (Mizushima et al. 2001, Suzuki et al. 2001).”

“PINK1 also phosphorylates ubiquitin, which further enhances Parkin activity (Kane et al. 2014).”

“…that OPTN and TBK1 are involved in mitophagy downstream from PINK1 and Parkin, is particularly interesting because mutations in both OPTN and TBK1 are causative for rare forms of familial amyotrophic lateral sclerosis (ALS) (Cirulli et al. 2015, Freischmidt et al. 2015, Maruyama et al. 2010).”

“Beclin1 is a component of the nucleation complex, along with ATG14, lipid kinase VPS34/PI3KIII, and VPS15/PIK3R4 (Itakura et al. 2008, Matsunaga et al. 2009, Sun et al. 2008, Zhong et al. 2009).”

“Beclin1 is a component of the nucleation complex, along with ATG14, lipid kinase VPS34/PI3KIII, and VPS15/PIK3R4 (Itakura et al. 2008, Matsunaga et al. 2009, Sun et al. 2008, Zhong et al. 2009).”

“These results indicated that basal autophagy is necessary for postnatal spine pruning (Tang et al. 2014).”

“When activated, ULK1 phosphorylates other autophagy pathway components, including Beclin1 (BECN1) and ATG9 (Feng et al. 2014, Kamada et al. 2000, Russell et al. 2013, Zhou et al. 2017).”

“The molecular players in this pathway have been well-defined from decades of elegant work in yeast (Ohsumi 2014).”

“…plasma membrane (Hollenbeck 1993; Ravikumar 2010), mitochondria (Hailey et al. 2010), Golgi (van der Vaart et al. 2010), ER (Hamasaki et al. 2013, Hayashi-Nishino et al. 2009, Ylä-Anttila et al. 2009), and recycling endosomes (Puri et al. 2018), has been implicated in autophagy at some point.”

“The ATG12-ATG5 conjugate, along with ATG16L1, acts as the E3-like enzyme to conjugate mATG8s to phosphatidylethanolamine (PE) (Mizushima et al. 2001, Suzuki et al. 2001).”

“Beclin1 is a component of the nucleation complex, along with ATG14, lipid kinase VPS34/PI3KIII, and VPS15/PIK3R4 (Itakura et al. 2008, Matsunaga et al. 2009, Sun et al. 2008, Zhong et al. 2009).”

“The nucleation complex generates PI3P, an important component of the autophagosome membrane during biogenesis (Kihara et al. 2001, Obara et al. 2006).”

“J. Neurosci 23(4):1254–64 [PubMed: 12598614] Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, et al. 2015 Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.”

“Similarly, Fam134b−/− mice exhibit sensory neuropathy and an age-dependent loss of sensory axons, with impaired ER turnover apparent at the cellular level (Khaminets et al. 2015).”

“This allows PINK1 to phosphorylate Parkin, leading to Parkin recruitment and activation (Kondapalli et al. 2012, Shiba-Fukushima et al. 2012).”

“Knockout mice exhibit relatively subtle phenotypes, including altered synaptic excitability and decreased dopamine release, which do not clearly model human PD (Goldberg et al. 2003, Kitada et al. 2007, Perez & Palmiter 2005).”

“…at multiple points in the pathway, including autophagosome biogenesis (De Pace et al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport (Nicolas et al. 2018, Wong & Holzbaur 2014b), and autophagosomelysosome…”

“The step-wise autophagosome biogenesis pathway elucidated in yeast and mammalian cell culture (Itakura & Mizushima 2010, Koyama-Honda et al. 2013) appears to be consistent with the pathway for biogenesis in the distal axon (Maday & Holzbaur 2014).”

“Dynein is recruited to autophagosomes by RAB7 and RILP (Cheng et al. 2015, Jordens et al. 2001, Wijdeven et al. 2016).”

“This feedforward mechanism leads to the rapid ubiquitination of OMM proteins by Parkin (Narendra et al. 2010b) that serve as a binding platform for ubiquitin-binding mitophagy receptors.”

“Several components of the nucleation complex also function in cellular processes other than autophagy (Liang et al. 2008, Lindmo & Stenmark 2006, Annu Rev Cell Dev Biol.”

“Around the time the autophagosome membrane fuses with itself, the biogenesis machinery dissociates from the fully formed autophagosome, with the exception of the mATG8s, which remain tightly associated with the limiting membrane (Mizushima et al. 2003).”

“…that OPTN and TBK1 are involved in mitophagy downstream from PINK1 and Parkin, is particularly interesting because mutations in both OPTN and TBK1 are causative for rare forms of familial amyotrophic lateral sclerosis (ALS) (Cirulli et al. 2015, Freischmidt et al. 2015, Maruyama et al. 2010).”

“Dendritic autophagy The GABARAP subfamily of mATG8s, as its name suggests, was initially identified to interact with GABAA receptors by yeast-two-hybrid screening (Wang et al. 1999).”

“However, driving dAtg8 overexpression pan-neuronally using earlier-expressing ELAV-Gal4 did not extend lifespan, suggesting that the age of autophagy ectopic induction is important (Simonsen et al. 2008).”

“…plasma membrane (Hollenbeck 1993; Ravikumar 2010), mitochondria (Hailey et al. 2010), Golgi (van der Vaart et al. 2010), ER (Hamasaki et al. 2013, Hayashi-Nishino et al. 2009, Ylä-Anttila et al. 2009), and recycling endosomes (Puri et al. 2018), has been implicated in autophagy at some point.”

“…et al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport (Nicolas et al. 2018, Wong & Holzbaur 2014b), and autophagosomelysosome fusion or acidification (Lie & Nixon 2018, Nixon et al. 2005) across disease…”

“These autophagosomes were then rapidly transported back to the cell body (Cheng et al. 2015, Lee et al. 2011, Maday & Holzbaur 2014, Maday et al. 2012).”

“Similarly, in human brain, mRNA levels of Atg5, Atg7, Beclin1, and GABARAPL2 decrease with age; however, correlated protein level decreases were not assessed (Lipinski et al. 2010, Shibata et al. 2006).”

“Supporting the importance of p62 in neurons, mutations in p62/SQSTM1 are implicated in ALS/FTD (frontotemporal dementia) and ataxia (Fecto et al. 2011, Haack et al. 2016).”

“Likewise, conditionally knocking out Atg7 in Purkinje cells using the Pcp2 promoter in mice did not appear to affect dendrites, but did lead to neuronal and axonal dystrophy, degeneration of axon terminals, and eventual neuronal death (Komatsu et al. 2007b).”

“VPS13 is a lipid transporter between ER and other membranes, raising the possibility that ATG2 also functions as a lipid transporter that supplies lipids to the growing autophagosomal membrane (Kumar et al. 2018).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript α-synuclein accumulation (Spencer et al. 2009).”

“Analysis of mitochondrial turnover in PINK1 knockout mice suggests that there are additional, PINK1-independent pathways leading to mitophagy in neurons under basal conditions (McWilliams et al. 2018), which remain to be more fully characterized.”

“This allows PINK1 to phosphorylate Parkin, leading to Parkin recruitment and activation (Kondapalli et al. 2012, Shiba-Fukushima et al. 2012).”

“Observations from both experimental models and post-mortem analysis of human tissues suggest that dysfunction of autophagy may be a common contributor to the pathogenic process across these diseases (recently reviewed by (Boland et al. 2018, Chu 2018)).”

“For example, non-selective axonal autophagy is differentially regulated than the selective removal of damaged mitochondria from the soma (Cornelissen et al. 2018, Devireddy et al. 2015, McWilliams et al. 2016, Sung et al. 2016).”

“Knockout mice exhibit relatively subtle phenotypes, including altered synaptic excitability and decreased dopamine release, which do not clearly model human PD (Goldberg et al. 2003, Kitada et al. 2007, Perez & Palmiter 2005).”

“One group reported localized mitophagy along the axons of hippocampal neurons upon induction of cellular stress via mitochondrial depolarization or ROS generation (Ashrafi et al. 2014).”

“Three-dimensional reconstructions of the ER in mouse brain show the dramatic extension of ER tubules throughout the soma, dendrites and axon of neurons in vivo (Wu et al. 2017).”

“However, the mATG8s have been implicated in this step (Tsuboyama et al. 2016).”

“One significant difference is that axonal autophagosomes form constitutively under fed conditions (Cheng et al. 2015, Lee et al. 2011, Maday & Holzbaur 2014, 2016; Maday et al. 2012, Stavoe et al. 2016), in contrast, to the induction of autophagy in nutrient-limiting conditions observed in many…”

“Knockout mice exhibit relatively subtle phenotypes, including altered synaptic excitability and decreased dopamine release, which do not clearly model human PD (Goldberg et al. 2003, Kitada et al. 2007, Perez & Palmiter 2005).”

“…multiple ER-associated proteins with LIR motifs that mediate binding to LC3-family proteins, including FAM134B/RETREG1 (reticulophagy regulator 1), reticulon 3L (RTN3), and CCPG1 (cell cycle progression 1) (Fumagalli et al. 2016, Grumati et al. 2018, Khaminets et al. 2015, Smith et al. 2018).”

“Beclin1 is a component of the nucleation complex, along with ATG14, lipid kinase VPS34/PI3KIII, and VPS15/PIK3R4 (Itakura et al. 2008, Matsunaga et al. 2009, Sun et al. 2008, Zhong et al. 2009).”

“Similarly, in human brain, mRNA levels of Atg5, Atg7, Beclin1, and GABARAPL2 decrease with age; however, correlated protein level decreases were not assessed (Lipinski et al. 2010, Shibata et al. 2006).”

“In contrast, ATG14 is specifically required for the proper localization of the nucleation complex to the forming autophagosome (Matsunaga et al. 2010); ATG14 also recruits other autophagosome biogenesis components to the initial autophagosome membrane, termed the isolation membrane in mammals.”

“This work was consistent with electron microscopy studies of primary rat sympathetic motor neurons identifying autophagic vesicles in distal growth cones (Bunge 1973).”

“Several components of the nucleation complex also function in cellular processes other than autophagy (Liang et al. 2008, Lindmo & Stenmark 2006, Annu Rev Cell Dev Biol.”

“…have demonstrated aging or disease-associated deficits at multiple points in the pathway, including autophagosome biogenesis (De Pace et al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport (Nicolas et al.…”

“While there are lysosomes present in the axon, they lack the full complement of degradative enzymes found in somal lysosomes (Cheng et al. 2018, Gowrishankar et al. 2015).”

“Deficits in intersecting pathways such as the ubiquitin-proteasome pathway and lysosomal degradation via chaperone-mediated autophagy are also likely to contribute to neurodegenerative disease (Scrivo et al. 2018).”

“In vitro studies indicate that p62 is sufficient to induce the clustering of ubiquitinated proteins, known as cargo nucleation, into aggregates that can be targeted by autophagy (Zaffagnini et al. 2018).”

“Thus, these data suggest that autophagy acts in dopamine neurons to restrict synaptic transmission (Hernandez et al. 2012).”

“Conversely, GFP-LC3 was rarely observed associated with axonal mitochondria in these experiments (Cai et al. 2012).”

“ATG4 also acts at the end of autophagy to cleave mATG8s from the cytosolic face of the completed autophagosome (Kauffman et al. 2018, Tanida et al. 2004).”

“These swellings contained ubiquitinated filamentous inclusions that were also observed in cell bodies (Friedman et al. 2012).”

“For example, mitochondrial ubiquitin ligase 1 (MUL1 or Mulan) has been proposed to function in a parallel pathway to Parkin in the clearance of damaged mitochondria (Yun et al. 2014).”

“While there are lysosomes present in the axon, they lack the full complement of degradative enzymes found in somal lysosomes (Cheng et al. 2018, Gowrishankar et al. 2015).”

“In Drosophila, autophagosome biogenesis also occurred at the neuromuscular junction (NMJ) in the distal axon of motor neurons (Neisch et al. 2017, Soukup et al. 2016).”

“Virtually every possible membrane source, including plasma membrane (Hollenbeck 1993; Ravikumar 2010), mitochondria (Hailey et al. 2010), Golgi (van der Vaart et al. 2010), ER (Hamasaki et al. 2013, Hayashi-Nishino et al. 2009, Ylä-Anttila et al. 2009), and recycling endosomes (Puri et al. 2018),…”

“Upon stimulation with low-dose NMDA, dendritic spines displayed an increase in GFP-LC3 puncta.”

“Multiple degradative pathways are at work in neurons, such as the degradation of misfolded proteins via the ubiquitin-proteasome pathway (Bingol & Sheng 2011).”

“However, age appears to affect neuronal autophagy more variably than other tissues (Chang et al. 2017).”

“In transgenic mice overexpressing amyloid precursor protein (APP) and heterozygous for a Beclin1 deletion, synapses and dendrites degenerated in neocortex and hippocampus and layer II neurons of the entorhinal cortex were lost (Pickford et al. 2008).”

“Genetic studies indicate that FAM134B, an ERphagy receptor, is required to maintain neuronal homeostasis, as mutations cause a sensory and autonomic neuropathy known as HSAN-II (Kurth et al. 2009).”

“…outer membrane by PI3P phosphatases (Cebollero et al. 2012) and mATG8s are removed from the outer membrane by ATG4 (Kauffman et al. 2018, Nair et al. 2012, Yu et al. 2012), possibly destabilizing the association of other autophagy components with the cytosolic face of the autophagosomal membrane.”

“The LC3-II/LC3-I ratio also decreased with age (Glatigny et al. 2019).”

“Additionally, overexpression of Atg1 increased NMJ synaptic bouton number in an autophagy-dependent manner (Shen & Ganetzky 2009).”

“Of note, a loss-of-function mutation in the Atlastin ATL1 is causal for SPG3A, a hereditary spastic paraplegia (Namekawa et al. 2007).”

“Dynein is recruited to autophagosomes by RAB7 and RILP (Cheng et al. 2015, Jordens et al. 2001, Wijdeven et al. 2016).”

“The step-wise autophagosome biogenesis pathway elucidated in yeast and mammalian cell culture (Itakura & Mizushima 2010, Koyama-Honda et al. 2013) appears to be consistent with the pathway for biogenesis in the distal axon (Maday & Holzbaur 2014).”

“Neuron-specific knock-out of FIP200 in mice using the Nestin promoter triggered neuronal loss of Purkinje cells and granular cells, spongiosis in the cerebellar white matter, axonal and dendritic degeneration in Purkinje cells, axonal swelling, and accumulation of ubiquitinpositive aggregates (Liang et al. 2010).”

“For example, non-selective axonal autophagy is differentially regulated than the selective removal of damaged mitochondria from the soma (Cornelissen et al. 2018, Devireddy et al. 2015, McWilliams et al. 2016, Sung et al. 2016).”

“The nucleation complex generates PI3P, an important component of the autophagosome membrane during biogenesis (Kihara et al. 2001, Obara et al. 2006).”

“One significant difference is that axonal autophagosomes form constitutively under fed conditions (Cheng et al. 2015, Lee et al. 2011, Maday & Holzbaur 2014, 2016; Maday et al. 2012, Stavoe et al. 2016), in contrast, to the induction of autophagy in nutrient-limiting conditions observed in many…”

“Observations from both experimental models and post-mortem analysis of human tissues suggest that dysfunction of autophagy may be a common contributor to the pathogenic process across these diseases (recently reviewed by (Boland et al. 2018, Chu 2018)).”

“2009), and recycling endosomes (Puri et al. 2018), has been implicated in autophagy at some point.”

“Conversely, transcriptome and proteome analysis in rat brain did not detect significant changes in autophagy pathway components between six months and 24 months (Ori et al. 2015).”

“One mechanism for turnover is ERphagy (also referred to as reticulophagy), the selective removal of ER segments by autophagy (Grumati et al. 2018).”

“This robust retrograde trafficking of autophagosomes has been confirmed in vivo in C. elegans (Stavoe et al. 2016) and Drosophila (Neisch et al. 2017), where the STRIPAK complex was implicated as a key regulatory factor.”

“Conversely, transcriptome and proteome analysis in rat brain did not detect significant changes in autophagy pathway components between six months and 24 months (Ori et al. 2015).”

“…every possible membrane source, including plasma membrane (Hollenbeck 1993; Ravikumar 2010), mitochondria (Hailey et al. 2010), Golgi (van der Vaart et al. 2010), ER (Hamasaki et al. 2013, Hayashi-Nishino et al. 2009, Ylä-Anttila et al. 2009), and recycling endosomes (Puri et al. 2018), has…”

“Several accessory transmembrane proteins have recently been discovered, such as VMP1 and TMEM41B (Moretti et al. 2018, Morita et al. 2018), which primarily localize to the ER.”

“GABARAP was then subsequently found to be important for GABAA receptor intracellular trafficking (Leil 2004), but the cellular mechanism of GABARAP regulation of GABAA receptor trafficking remains unclear.”

“…including autophagosome biogenesis (De Pace et al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport (Nicolas et al. 2018, Wong & Holzbaur 2014b), and autophagosomelysosome fusion or acidification (Lie &…”

“Additionally, mitochondrial anchoring protein syntaphilin (SNPH) is released from axonal mitochondria upon stress, allowing their retrograde transport out of the axon (Lin et al. 2017).”

“After autophagosome closure, PI3P is removed from the outer membrane by PI3P phosphatases (Cebollero et al. 2012) and mATG8s are removed from the outer membrane by ATG4 (Kauffman et al.”

“Sci 113(24):E3349–58 [PubMed: 27247382] Moretti F, Bergman P, Dodgson S, Marcellin D, Claerr I, et al. 2018 TMEM41B is a novel regulator of autophagy and lipid mobilization.”

“These data indicate that autophagy selectively regulates surface expression of GABAA receptors, suggesting that autophagy could modulate neuronal excitation and inhibition (Rowland 2006).”

“Genetic studies indicate that FAM134B, an ERphagy receptor, is required to maintain neuronal homeostasis, as mutations cause a sensory and autonomic neuropathy known as HSAN-II (Kurth et al. 2009).”

“Analogously, knockdown of Beclin1 in M17 human neuroblastoma cells resulted in increased aggregations of α-synuclein oligomers (Yu et al. 2009).”

“Similarly, in rat primary hippocampal neurons, stimulation with KCl or NMDA induced axonal autophagy (Shehata et al. 2012, Wang et al. 2015).”

“Additionally, conditional knock-out of Atg7 in dopaminergic neurons using the DAT, EN, or TH promoters produced neuron loss, loss of striatal dopamine, accumulation of ubiquitin- and p62-containing inclusions, and accumulation of α-synuclein in vivo (Ahmed et al. 2012, Sato et al. 2018).”

“…leads to accumulation of both p62 and ubiquitinated proteins. p62 appears to sit at a crucial juncture between the ubiquitin proteasome and selective autophagy by detecting the buildup of ubiquitinated substrates (Danieli & Martens 2018), suggesting a key role in regulation of protein turnover.”

“…acts downstream from known Atg genes (Lu et al. 2011, Tian et al. 2010), yielded p62 aggregations and ubiquitin-positive inclusions in brain and spinal cord extracts, a reduction of pyramidal and motor neurons, axonal degeneration, and accumulation of TDP43 aggregates in neurons (Zhao et al. 2013).”

“Supporting the importance of p62 in neurons, mutations in p62/SQSTM1 are implicated in ALS/FTD (frontotemporal dementia) and ataxia (Fecto et al. 2011, Haack et al. 2016).”

“Studies to date have demonstrated aging or disease-associated deficits at multiple points in the pathway, including autophagosome biogenesis (De Pace et al. 2018, Rui et al. 2015, Stavoe & Holzbaur 2018), cargo-loading (Martinez-Vicente et al. 2010, Rudnick et al. 2017), intracellular transport…”

“In vivo studies support a role for ALFY in aggrephagy, as the Drosophila mutant blue cheese demonstrates accumulation of ubiquitin-positive inclusions, neurodegeneration, and shortened lifespan (Finley et al. 2003).”

“Baseline defects in autophagy were not observed, but an exogenous aggregation-prone substrate accumulated more rapidly in Alfy knockout MEFs (Dragich et al. 2016).”

“ALFY (autophagy-linked FYVE protein, also known as WDFY3 for WD repeat and FYVE domain-containing protein) is a large scaffolding molecule that binds to p62, the ATG8 proteins LC3C and the GABARAPs, and ATG5, a component of the core autophagy machinery (Lystad et al. 2014).”

“After autophagosome closure, PI3P is removed from the outer membrane by PI3P phosphatases (Cebollero et al. 2012) and mATG8s are removed from the outer membrane by ATG4 (Kauffman et al. 2018, Nair et al. 2012, Yu et al. 2012), possibly destabilizing the association of other autophagy components with the cytosolic face…”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Matsunaga et al. 2009, Yan et al. 2009, Zhong et al. 2009).”

“In the converse experiment in chick embryonic DRG neurons, when axon outgrowth was blocked with cytochalasin-E, retrograde transport of axonal autophagosomes increased threefold (Hollenbeck & Bray 1987).”

“In humans, a missense mutation in WDR81 is associated with the rare neurodevelopmental condition known as CAMRQ for cerebellar ataxia, mental retardation, and disequilibrium syndrome (Gulsuner et al. 2011).”

“In Drosophila, autophagosome biogenesis also occurred at the neuromuscular junction (NMJ) in the distal axon of motor neurons (Neisch et al. 2017, Soukup et al. 2016).”

“For example, non-selective axonal autophagy is differentially regulated than the selective removal of damaged mitochondria from the soma (Cornelissen et al. 2018, Devireddy et al. 2015, McWilliams et al. 2016, Sung et al. 2016).”

“Although the number of autophagosomes increased in the axon, NMDA treatment did not appear to affect retrograde transport of autophagosomes (Katsumata et al. 2010).”

“Of note, a loss-of-function mutation in the Atlastin ATL1 is causal for SPG3A, a hereditary spastic paraplegia (Namekawa et al. 2007).”

“For example, non-selective axonal autophagy is differentially regulated than the selective removal of damaged mitochondria from the soma (Cornelissen et al. 2018, Devireddy et al. 2015, McWilliams et al. 2016, Sung et al. 2016).”

“Recently identified pathways may also contribute to the clearance of misfolded or aggregated proteins in neurons, such as the MAGIC (mitochondria as guardian in cytosol) pathway involving import of misfolded proteins into mitochondria (Ruan et al. 2017).”

“WDR81 (WD repeat domain 81) can bind directly to LC3, but also interacts with p62, and has been proposed to facilitate the ability of p62 to bind to aggregated and ubiqutinated proteins (Liu et al. 2017).”

“As in worms, these defects in autophagy mutants were due to incorrect synaptic formation, not precocious degeneration or synaptic retraction (Wairkar et al. 2009).”

“Conditionally knocking out mTOR in GABAergic precursors increased autophagy in those cells and suppressed their proliferation, leading to a reduction in cortical interneurons (Ka et al. 2017).”

“Similarly, in the Zebrafish photoreceptor, synaptojanin, a lipid phosphatase and EndophilinA interactor, is necessary for autophagy (George et al. 2016).”

“In PC12 cells, primary hippocampal neurons, and Xenopus oocytes, GABARAP lipidation was required for increased surface expression of GABAA receptors (Chen et al. 2007).”

“In SH-SY5Y cells, an in vitro cell line model of neurons, induction of autophagy with Tri-ortho-cresyl phosphate (TOCP) also inhibited neurite outgrowth (Chen et al. 2013).”

“Similarly, mice carrying a homozygous missense mutation in WDR81 exhibited Purkinje cell and photoreceptor cell death (Traka et al. 2013).”

“In Drosophila, knockdown of autophagy genes reduced dendritic arbor growth and terminal branching in multidendritic sensory neurons in vivo (Clark et al. 2018).”

“This hypothesis is further supported by the observation that mutations in many of the proteins involved in autophagy are sufficient to cause neurodevelopmental or neurodegenerative disease, including PINK1, Parkin, OPTN, TBK1, ATL1, SQSTM1, and WDR81 as discussed above, as well as ATG5, AP4, HTT, WIPI4, and DYNC1H1 (r…”