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Cited by 126Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyNuclear Receptors and Signaling

Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice

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Sato, Shigeto, Uchihara, Toshiki, Fukuda, Takahiro, Noda, Sachiko, Kondo, Hiromi, Saiki, Shinji, Komatsu, Masaaki, Uchiyama, Yasuo +2 more·2018·Scientific Reports
DOI 10.1038/s41598-018-21325-wPMC PMC5809579
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Abstract

Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson’s disease (PD). Here, we characterize dopamine (DA) neuron–specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as “seeds” and can potentially be cause of LB formation.

AI snapshot

Written from the paper’s full text.

TL;DR

Dopamine neuron–specific Atg7 deletion in mice causes age-related p62 inclusions that precede synuclein accumulation, Lewy-like pathology, loss of TH neurons, and motor dysfunction. The findings suggest autophagic p62 aggregates may serve as “seeds” for Lewy body formation.

Key findings

  • Atg7flox/flox:TH-Cre mice had 13.54 ± 2.27% residual Atg7 in midbrain versus controls and developed motor coordination impairment around 100 weeks, with apparent deficits around 110 weeks, including frequent hindlimb slips on the runway and reduced rotarod fall latency.
  • p62-positive inclusions appeared in substantia nigra dopaminergic neurons by 2 months, increased in number and size with age, and were mainly localized outside the soma along neurites; synuclein accumulation was observed around 9 months and colocalized with p62 inclusions, with 89.30 ± 1.65% of synuclein inclusions located in TH fibers (n = 5, each 2 slices).
  • In 120-week-old mice, Atg7flox/flox:TH-Cre mice had fewer TH neurons than controls, most prominently in the center area of substantia nigra pars compacta (SNcc) (n = 4 cKO; n = 5 control), and HPLC showed reduced striatal DA and metabolites (n = 3 per group; *P = 0.05).
  • Ultrastructural analysis showed electron-dense filamentous inclusions in SN somata and neurites containing mitochondria and autophagosome-like structures; the authors speculate p62 aggregates containing mitochondria represent early Lewy body biogenesis.

Methods

  • Generated tyrosine hydroxylase (TH) neuron–specific Atg7 conditional knockout mice (Atg7flox/flox:TH-Cre) by crossing Atg7flox/flox mice with TH-Cre mice; controls were Atg7flox/flox mice.
  • Assessed locomotor behavior from 90 to 120 weeks using an accelerating rotarod (3 to 35 rpm over 5 min) and a narrow beam runway test; performed immunoblot, immunohistochemistry, immunofluorescence, electron microscopy/immunoelectron microscopy, and HPLC of dorsal striatum.
  • Statistical significance was determined by Student’s t-test; behavioral tests used n = 10 per genotype, TH neuron counts used n = 4 cKO and n = 5 control, and HPLC used n = 3 per group.

Limitations

  • The paper states that many questions remain about Lewy body formation, that none of the current genetic PD mouse models recapitulates all features of PD, and that only a few develop mild DA neurodegeneration; it also notes that compensatory mechanisms during development may make degenerative phenotypes hard to observe over the mouse lifespan.
  • The paper states that the reason the significant decrease in dopamine was not accompanied by concomitant reductions in DOPAC and HVA was not clarified, and it describes the p62 “seed” role as speculation.
  • Evident from the text: survival was not observed over the entire lifespan, some synuclein data at early stages are reported as “data not shown,” and terminal analyses used small sample sizes (n = 3–5 per group).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41598-018-21325-w

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    These inclusions are observed not only within the soma but also outside the soma.

    “Interestingly, we observed these inclusions not only within the soma, but also outside the soma (Fig. 3D lower panel).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Most inclusions localize in neurites.

    “To determine the localization of these inclusions, we analyzed many samples by confocal microscopy, and found that most inclusions localized in neurites, as demonstrated in Fig. 2D.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In Atg7flox/flox:TH-Cre mice, locus coeruleus neurons contain eosinophilic aggregates characteristic of Lewy bodies.

    “In Atg7flox/flox:TH-Cre mice, these neurons contained 7 eosinophilic aggregates, which are characteristic of LBs (Fig. 1Da).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The level of synuclein is increased in the midbrain of Atg7flox/flox:TH-Cre mice.

    “Furthermore, the level of synuclein increased in the midbrain of Atg7flox/flox:TH-Cre mice (Fig. 3B and C).”
    Quote in the paperSubstantial claim
  • Findingown data

    p62-positive aggregates are present along neurites of dopaminergic neurons.

    “Specifically, we labeled dopaminergic neurons with TH antibody (Fig. 2D red) and followed individual fibers, revealing that p62-positive aggregates (Fig. 2D green) were present along neurites.”
    Quote in the paperSubstantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    Atg7flox/flox:TH-Cre mice begin to show impairment in motor coordination tasks around 100 weeks and apparent motor behavioral deficits around 110 weeks.

    “Although Atg7flox/flox:TH-Cre mice have not yet been observed over the entire lifespan, they began to show impairment in motor coordination tasks around 100 weeks and apparent motor behavioral deficits around 110 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No neuronal loss is observed in young mice, which did not exhibit motor dysfunction.

    “No neuronal loss was observed in young mice, which did not exhibit motor dysfunction (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p62 inclusions are present along TH fibers and mainly located in the branch of dopaminergic neurons.

    “P62 inclusions were present along the TH fibers, and were mainly located in the branch of dopaminergic neurons (Fig. 2Cb).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    At higher magnification, these inclusions have multiple cavities.

    “When we observed these inclusions at higher magnification, they have multiple cavities (Fig. 3E), consistent with the results of ultrastructural analysis (Fig. 2Ed).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    p62-positive inclusions are present in 2-month-old Atg7flox/flox:TH-Cre mice, whereas no aggregates are seen in Atg7flox/flox mice even at 18 months.

    “In contrast to Atg7flox/flox mice, in which no aggregates were seen even at the age of 18 months (Fig. 2Ab), p62-positive inclusions were present in 2-month-old Atg7flox/flox:TH-Cre mice (Fig. 2Aa).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These inclusions are observed in TH-positive neurons and contain ubiquitin and p62.

    “In addition, these inclusions were observed in TH-positive neurons (Fig. 1Db), including ubiquitin (Fig. 1Dc) and p62 (Fig. 1Dd).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The level of endogenous synuclein protein increased at around 9 months in cell bodies and neurites of Atg7flox/flox:TH-Cre mice, and these accumulated synuclein deposits contained p62 positive aggregates.

    “In our careful observation of Atg7flox/flox:TH-Cre mice, we found that the level of endogenous synuclein protein increased at around 9 months in cell bodies and neurites (Fig. 3A,B and C), and these accumulated synuclein deposits contained p62 positive aggregates (Fig. 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 18-month-old Atg7flox/flox:TH-Cre mice, p62 inclusions are larger and mainly localized outside the soma.

    “In 18-month-old mice, p62 inclusions were larger (Fig. 2Ae and B) and mainly localized outside the soma (Fig. 2Ac).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 2-month-old Atg7flox/flox:TH-Cre mice, p62 and ubiquitin accumulate in the midbrain, whereas synuclein does not accumulate at this stage.

    “Notably, Western blotting revealed p62 and ubiquitin accumulations in the midbrain of 2 month-old Atg7flox/flox:TH-Cre mice, whereas synuclein did not accumulate in the midbrain, at least at this stage (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Atg7flox/flox:TH-Cre mice are viable at birth and indistinguishable in appearance from littermates, and their survival rate is not markedly diminished.

    “Atg7flox/flox:TH-Cre mice were viable at birth and indistinguishable in appearance from their littermates, and their survival rate was not markedly diminished.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Brain-specific deletion of Atg5 or Atg7 in mice reveals a critical role of autophagy in the removal of aggregated proteins.

    “Although the phenotypes of mice harboring brain-specific deletion of Atg5 or Atg7 reveal the critical role of autophagy in the removal of aggregated proteins7,8”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006). source

      Not checked in the free run.

    • cites [8] Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    DA neuron-specific autophagy deficiency leads to restrictive presynaptic accumulation of synuclein in the dorsal striatum.

    “Friedman et al.9 demonstrated that DA neuron-specific autophagy deficiency leads to the restrictive presynaptic accumulation of synuclein in the dorsal striatum, suggesting that impaired autophagy plays a role in PD pathogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Friedman, L. G. et al. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32, 7585–7593 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Parkinson's disease is characterized by the loss of nigrostriatal dopamine neurons and the formation of intracellular Lewy bodies, which consist primarily of α-synuclein and ubiquitin.

    “Parkinson’s disease (PD), the most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons and the formation of intracellular Lewy bodies (LBs), which consist primarily of α-synuclein (hereafter referred to as synuclein) and ubiquitin1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839–840 (1997). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    p62 is present in neuronal inclusions of individuals with Alzheimer's disease and other neurodegenerative diseases.

    “Indeed, p62 is present in neuronal inclusions of individuals with Alzheimer’s disease and other neurodegenerative diseases11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Bartlett, B. J. et al. p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. Autophagy 7, 572–583 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    p62 is a ubiquitin- and LC3-binding protein that functions as a selective autophagy adaptor/receptor for degradation of ubiquitinated substrates.

    “In this context, the stress-inducible protein p62 (encoded by the gene Sqstm1) is of importance because it is the ubiquitin- and LC3-binding protein that functions as a selective autophagy adaptor/receptor for degradation of ubiquitinated substrates10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.

    “Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis5,6,15, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29, 13578–13588 (2009). source

      Not checked in the free run.

    • cites [6] Yu, W. H. et al. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol 175, 736–747 (2009). source

      Not checked in the free run.

    • cites [15] Ahmed, I. et al. Development and characterization of a new Parkinson’s disease model resulting from impaired autophagy. J Neurosci 32, 16503–16509 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autophagosome-like structures have been previously reported in Atg7-deficient brains.

    “In fact, these autophagosome-like structures were previously reported in Atg7-deficient brains14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Komatsu, M. et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 104, 14489–14494 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Loss of autophagy induces synuclein accumulation and formation of Lewy bodies in DA neurons.

    “Thus, loss of autophagy induces synuclein accumulation and formation of LBs, similar to the pathology observed in DA neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LB-like synuclein aggregates resist degradation and impair autophagy.

    “Furthermore, LB-like synuclein aggregates resist degradation and impair autophagy20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R. & Lee, V. M. Lewy body-like alpha-synuclein aggregates resist degradation and impair macroautophagy. J Biol Chem 288, 15194–15210 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Homeostasis of p62 is strictly regulated by autophagy in the brain, and dysregulation of autophagy causes formation of p62 aggregates.

    “It is well known that homeostasis of p62 is strictly regulated by autophagy in the brain10, and that dysregulation of autophagy causes formation of p62 aggregates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Loss of autophagy in dopaminergic neurons results in Lewy pathology and motor dysfunctions associated with aging.

    “In this study, we carried out detailed observations of Atg7-deficient mice, and observed a loss of autophagy in dopaminergic neurons, resulting in Lewy pathology and motor dysfunctions associated with aging.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The synuclein antibody efficiently detects endogenous mouse synuclein.

    “Our synuclein antibody efficiently detects endogenous mouse synuclein, and a virtual slide system could be used to observe neurons extensively.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    DA neurons have long hyper-branched projection axons that innervate wide areas in the brain.

    “DA neurons have a unique structural characteristic, long hyper-branched projection axons, that innervate wide areas in the brain22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Sulzer, D. & Surmeier, D. J. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord 28, 715–724 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The extent to which autophagy contributes to synuclein degradation depends on the presence of mutations.

    “The protein catabolic pathways that regulate synuclein degradation have been discussed by multiple authors4,16,17, and the extent to which autophagy contributes to synuclein degradation depends on the presence of mutations18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG conjugation systems including Atg7 are not absolutely essential for autophagosome formation.

    “But, as to autophagosome formation, ATG conjugation systems including Atg7 are not absolutely essential13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Tsuboyama, K. et al. The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354, 1036–1041 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    One explanation for the lack of concomitant reductions in DOPAC and HVA may be presynaptic dysfunction in Atg7-deficient mice.

    “Until now, we did not clarify the reason, but one of the explanation may be presynaptic dysfunction in Atg7-deficient mice9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Friedman, L. G. et al. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci 32, 7585–7593 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bedford et al. reported deposits of mitochondria in early LBs (pale bodies) in PD patients.

    “and Bedford et al. also reported deposits of mitochondria in early LBs (pale bodies) in PD patients26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Bedford, L. et al. Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28, 8189–8198 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Electron microscopic analysis by Gai et al. revealed that many mitochondria are concentrated in the early forms of LBs.

    “Electron microscopic analysis by Gai et al. revealed that many mitochondria are concentrated in the early forms of LBs25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Gai, W. P. et al. In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. Exp Neurol 166, 324–333 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Atg7-deficient mice demonstrate typical Lewy pathology, including endogenous synuclein and neuronal loss, which resembles PD.

    “Our Atg7-deficient mice demonstrate typical Lewy pathology, including endogenous synuclein and neuronal loss, which resembles PD.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Depolarized mitochondria are ubiquitylated by Parkin, recognized by p62, transported via microtubules to aggregates, and degraded by autophagy.

    “During mitochondrial degradation in cultured cells, depolarized mitochondria cluster with p6224. Depolarized mitochondria are ubiquitylated by Parkin, recognized by p62, transported via microtubules to aggregates, and degraded by autophagy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Okatsu, K. et al. p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15, 887–900 (2010). source

      Not checked in the free run.

30 of 30

  • The paper relies on this without support.

    The relationship between impaired autophagy and Lewy body formation and the in vivo process of formation remains unknown.

    “Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown.”

  • The paper relies on this without support.

    In DA neurons, no detailed reports to date have examined endogenous synuclein accumulation in dopaminergic cell bodies and neurites associated with Lewy pathology.

    “In DA neurons, the primary site of endogenous pathology, no detailed reports to date have examined the endogenous synuclein accumulation in dopaminergic cell bodies and neurites, which is associated with Lewy pathology.”

  • The paper relies on this without support.

    The mechanisms underlying age-related progression and intracellular localization of p62 inclusions in dopaminergic neurons remain elusive.

    “However, the mechanisms underlying age-related progression and intracellular localization of these inclusions in dopaminergic neurons remain elusive.”

  • The paper relies on this without support.

    It remained unclear how synuclein accumulation is associated with PD pathology.

    “Previous in vivo analysis of DA neurons suggested that synuclein regulation is linked to autophagy9,15, but it remained unclear how synuclein accumulation is associated with PD pathology.”

  • The paper relies on this without support.

    Most genetically modified mouse PD models do not exhibit neuronal loss.

    “To date, many genetically modified mice have been developed as PD models, but most of them do not exhibit neuronal loss.”

  • The paper relies on this without support.

    None of the current genetic PD models in mouse recapitulates all features of PD.

    “None of the current genetic PD models in mouse recapitulates all features of PD.”

  • The paper relies on this without support.

    Only a few genetic PD models develop mild DA neurodegeneration.

    “Additionally, only a few of these models develop mild DA neurodegeneration.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting reports of dopamine metabolite reductions

    Major

    The Results state that DOPAC and HVA levels were reduced in knockout mice, but the Discussion says the dopamine decrease was not accompanied by reductions in those metabolites.

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Authors
Sato, S., Uchihara, T., Fukuda, T., Noda, S., Kondo, H., Saiki, S., Komatsu, M., Uchiyama, Y., Tanaka, K., & Hattori, N.
Affiliations
  • Juntendo University (JP)
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Jikei University School of Medicine (JP)
  • Niigata University (JP)
Corresponding author
  • Sato, Shigeto
  • Hattori, Nobutaka
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-02-12
Volume
8
Issue
1
Pages
2813-2813
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-21325-w
PMC
PMC5809579
OpenAlex
W2800535259
Semantic Scholar
515cfb0f749654c17b9ffeb4dc295ee16d8ba92c
Cited by
125
References
29
Citations by year
2026: 6 · 2025: 13 · 2024: 14 · 2023: 10 · 2022: 13 · 2021: 20 · 2020: 23 · 2019: 19 · 2018: 7
FWCI
11.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Japan Society for the Promotion of Science (25111006, 17H03555, 25111007, 17K07797, 15H04843, 18H04043, 26000014, 16K14572)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
autophagy, dopaminergic neurons, Lewy bodies, Parkinson's disease, synuclein, p62, neuronal inclusions, aging, motor impairment, autophagy-deficient mice, protein aggregation, neurodegeneration
MeSH terms
Animals, Autophagy, Brain, Inclusion Bodies, Disease Models, Animal, Parkinson Disease, Transcription Factors, Neurites, Lewy Bodies, Motor Skills Disorders, Mice, Transcription Factor TFIIH, Synucleins, Dopaminergic Neurons

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