©2008 Landes Bioscience. Do not distribute.
Addendum to: Stern ST, Zolnik BS, McLeland CB, Clogston J, Zheng J, McNeil SE.
Induction of autophagy in porcine kidney cells by quantum dots: a common cellular
response to nanomaterials? Toxicol Sci 2008; 106:140–52; PMID: 18632727;
Nanotechnology is the control and manipulation of materials
in the size range of 1–100 nm. Due to increasing research into
the potential beneficial applications of nanotechnology, there
is an urgent need for the study of possible health risks. Several
researchers, including those in our laboratory, have demonstrated
elevated levels of autophagic vacuoles upon exposure of cells to
certain nanomaterials, including carbon- and metal-based nanopar-
ticles. While this apparent increase in autophagic activity may be an
appropriate cellular response toward nanomaterial clearance, often
the interaction between nanomaterials and the autophagy pathway
is disruptive, resulting in severe morphological changes and
coincident cell death. Interestingly, epidemiological studies have
identified an association between exposure to combustion-derived
ambient particles (which are predominantly nanoscale) and neuro-
logical conditions with Alzheimer’s and Parkinson’s disease-like
pathologies. Becuse impaired autophagy may play an important
role in the pathogenesis of these and other diseases, it is intriguing
to speculate about the plausible involvement of nanoscale particu-
lates in this process. The interaction of nanomaterials with the
autophagy pathway, and the potential negative consequences of
resulting autophagy dysfunction, should be explored further.
Nanotechnology is the control and manipulation of materials in
the size range of 1–100 nm, or nanomaterials. In addition to nanoma-
terials engineered via nanotechnology, nanomaterials occur naturally
and as the result of combustion processes. Due to increasing research
into the beneficial applications of nanotechnology, there is an
urgent need to clarify potential health risks. Recently, our laboratory
demonstrated increased autophagic vacuolization in porcine renal
proximal tubules exposed to engineered nanomaterials, specifically
polyethylene glycol-coated quantum dots with different core compo-
sitions.1 Autophagy is a lysosomal mechanism by which cellular
organelles are recycled and long-lived proteins are degraded, comple-
menting the breakdown of short-lived proteins by the proteasome.2
Autophagy is proposed as a pathway of programmed cell death (Type
II) similar in homeostatic function to apoptosis (Type I).3 There are
many examples in the literature of nanoscale particulates, such as
quantum dots, inducing elevated levels of autophagic vacuoles in
both animal and human cell culture models.4-8 Such nanomaterials
include: nanoscale carbon black, fullerene and fullerene derivatives,
nanoscale neodymium oxide, and protein-coated quantum dots. The
induction of autophagic vacuoles in these instances was characterized
at the ultrastructural cellular level via electron microscopy detec-
tion of vacuoles in treated cells, through immunoblot detection of
LC3-I to LC3-II conversion (an established marker of autophagy
activity) in cell lysates, and/or cellular immunolabeling of punctate
LC3-II autophagosome incorporation. Elevated levels of autophagic
vacuoles are detected in nanoparticle-exposed mouse fibroblasts,
porcine renal proximal tubules, human vascular endothelial cells,
human mesenchymal cells, human non-small cell lung cancer cells
and human glioma cells.1,4-8 This diversity of nanomaterials and cell
models has led researchers to pose the question: Do nanomaterials
commonly interact with the autophagy pathway?9 Here, we add a
further question: What might be the consequences of this interac-
tion? Autophagy is considered a sensitive marker of cellular stress,
occurring in response to viral infection, unfolded proteins, starva-
tion, and oxidative stress.10 Thus, the interaction of nanomaterials
with the autophagy pathway may be an indication of altered cellular
homeostasis, the long-term consequences of which are unknown.
Nanoparticle interaction with the autophagy pathway appears to
follow a distinct course, one associated with dramatic cellular vacu-
olization, loss of cellular organelles, and cytotoxicity.1,4-8 Whereas
the increase in autophagic vacuoles in response to nanomaterials
may be an adaptive cellular response, aiding in both degradation
and clearance of potentially toxic nanomaterials, it is also possible
that nanomaterials cause a state of autophagic dysfunction that is
harmful. In the case of fullerene-induced cytotoxicity in a human
glioma cell line and nano neodymium oxide-induced cell death in
*Correspondence to: Stephan T. Stern; Nanotechnology Characterization Laboratory;
Advanced Technology Program; SAIC-Frederick, Inc.; NCI-Frederick; Frederick,
Maryland 21702 USA; Tel.: 301.846.6198; Fax: 301.846.6399; Email:
Submitted: 09/26/08; Revised: 10/01/08; Accepted: 10/06/08
Previously published online as an Autophagy E-publication:
Role for nanomaterial-autophagy interaction in neurodegenerative
Stephan T. Stern and Denise N. Johnson
Nanotechnology Characterization Laboratory; Advanced Technology Program; SAIC-Frederick, Inc.; NCI-Frederick; Frederick, Maryland USA
Key words: autophagy, nanomaterial, pollution, Alzheimer’s disease, Parkinson’s disease, neurodegeneration, nanotechnology
[Autophagy 4:8, 1097-1100; 16 November 2008]; ©2008 Landes Bioscience
©2008 Landes Bioscience. Do not distribute.
disease block chaperone-mediated autophagy, resulting in impaired
α-synuclein clearance.28 Studies also demonstrate that impairment
of autophagy alone can result in neurodegeneration in normal
mice,37,38 and AD-like pathology was observed in a recent study
1098Autophagy 2008; Vol. 4 Issue 8
upon blockade of autophagosome-lysosome fusion in rat primary
cortical neurons,27 highlighting the importance of constitutive
autophagy in maintaining neuronal homeostasis.
Pollution as a Risk Factor for Neurodegerative Disease
Whereas the underlying etiology of AD and PD are not well
understood, a complex interplay of both environment and genetic
susceptibility is thought to be involved.39 Recently, airborne pollu-
tion, of which a major component is nanoscale particulates,40 has
been identified as a potential environmental risk factor for both AD
and PD. In one study, increased AD-associated β-amyloid peptide
and PD-associated α-synuclein accumulation was observed in brains
from children and young adults who had lived in the high-pollution
area of Mexico City and died suddenly, compared with age-matched
controls from low-pollution areas.41 In addition to the protein accu-
mulation, the residents of Mexico City had evidence of increased
blood-brain barrier disruption and neuroinflammation. This study’s
findings were similar to those of a study of older adults, in which
higher levels of β-amyloid peptide and inflammatory markers were
also observed in the brain and olfactory bulb of Mexico City resi-
dents in comparison to low-pollution controls.42 These studies in
humans follow a similar study conducted in dogs, in which increased
β-amyloid, amyloid precursor protein and Alzheimer-associated
plaques were detected in brains from dogs in Mexico City compared
to low-pollution areas.43 Recently, another study identified children
from Mexico City as having reduced cognitive abilities in compar-
ison to children from low-pollution areas.44 Additionally, children
and dogs from the high-pollution areas have similar MRI-imaged
prefrontal white matter lesions. Upon examination, these frontal
lesions of the brains of dogs from the high-pollution areas are also
shown to have increased markers of brain inflammation and ultrafine
Hypothesis: Nanoparticle-Autophagy Interaction in
Epidemiological studies have specifically implicated the nanoscale
component of particulate air pollution in exacerbation of human
diseases, including cardiovascular and respiratory disease.45 The
greater toxicity of this particle fraction is thought to be due, in part,
to its increased lung distribution, reactive surface area, and potential
for translocation to other regions of the body. It is intriguing to
speculate that nanoscale pollution particulates may also influence
AD and PD susceptibility by impairment of autophagy (Fig. 1). In
support of this hypothesis, nanoscale carbon black and fullerene,
which are components of pollution particulates,40 alter autophagy
homeostasis in human endothelial cells and glioma cells, respec-
tively.4,8 Pollution particulates also alter the cytoskeleton of human
lung epithelial cells, which could disrupt vesicle trafficking and
autophagosome-lysosome fusion.46 One question that arises is how
might nanoscale particulates interfere with autophagy when they
enter the CNS following inhalation exposure. One possible mecha-
nism that has been suggested is via microtubule-mediated neuronal
transport of particles into the olfactory bulb.47 In agreement with
neuronal transport, dogs from the high-pollution areas in one of the
studies above had damage to the olfactory epithelium and a gradient
of pollution-associated metal deposition in the order: olfactory
mucosa > olfactory bulb > frontal cortex.43 Additionally, the study
human non-small cell lung cancer, suppression of the autophagy
pathway is protective.4,8
It should be stressed that it is not presently known whether
nanomaterial-induced autophagic vacuoles are evidence of increased
autophagy, impairment of existing autophagy, or both. Nanomaterials
may influence autophagy flux by generating oxidative stress, altering
gene regulation, interfering with the kinase-mediated regulatory
cascades, or interacting directly with the endosome/lysosome itself.1
It is possible that nanomaterials may be perceived by the cell as
an endosomal pathogen or an aggregation-prone protein, both of
which are commonly degraded by the autophagy pathway.11,12
Alternatively, nanomaterials may impede autophagy by inhibiting
lysosomal enzymes13 or disrupting cytoskeleton-mediated vesicle
trafficking,14 resulting in diminished autophagosome-lysosome
fusion. Nanoparticles certainly share properties with substances
known to cause lysosomal disorders,15 including lysosomal local-
ization,16,17 enzyme inhibiting ability,18,19 and biopersistence. For
example, a water-soluble fullerene derivative causes lysosome-over-
load nephrosis in rats, which is typically the result of inhibition of
lysosomal protein degradation.20 Additionally, ubiquinated proteins
accumulate concomitantly with nanomaterial-induced autophagic
vacuoles.7 Ubiquinated proteins accumulate in many disease states
associated with autophagy impairment, including muscle and neuro-
degenerative diseases.21-23 Nanomaterials also bind cellular structural
components,24 disrupting the cytoskeleton and potentially affecting
Autophagy and Neurodegenerative Disease
Studies suggest that autophagy is an important homeostatic
pathway that can influence the pathogenesis of several neurodegenera-
tive diseases, including Alzheimer disease (AD) and Parkinson disease
(PD).27,28 AD and PD are commonly referred to as proteinopa-
thies, because accumulation of protein aggregates, resulting from
impaired removal of mutated and/or misfolded proteins, are a
disease hallmark.29,30 Autophagy may be an important pathway for
processing of the implicated proteins, including amyloid β in AD
and α-synuclein in PD.31,32 Indeed, in addition to the character-
istic protein aggregates, the brains of AD and PD patients display
evidence of extensive autophagic activity, including accumula-
tion of autophagosomes, autophagolysosomes, and multilamellar
and multivesicular bodies.33,34 As mentioned above, this increase
in autophagic vacuoles could result from increased autophagy or
impairment of constitutive autophagy. In support of the latter, there
are substantial data suggesting that impaired autophagy may play an
important role in development of AD and PD. Decreased expres-
sion of the pro-autophagy protein Beclin 1 is detected in affected
brain regions of Alzheimer’s patients, and in a mouse model of AD,
diminution of Beclin 1 expression results in increased amyloid β
deposition and neuronal pathology, whereas enhancement of Beclin
1 expression is protective.35 The most common mutation associ-
ated with familial AD is in presenilin-1, the gene product of which
plays a role in autophagic vacuole-lysosome fusion.36 In the case of
PD, some mutant α-synucleins associated with familial forms of the
©2008 Landes Bioscience. Do not distribute.
may be a common cellular response for many nanoscale materials. In
addition to the established paradigms of nanomaterial toxicity, such
as oxidative stress and inflammation,48 the potential consequences of
nanomaterial interaction with the autophagy pathway also deserves
examination. Apart from neurodegeneration, autophagy dysfunction
is thought to be involved in a variety of other conditions, including
cancer, metabolic disorders, infection, and myopathies.49 Thus,
nanomaterial-autophagy interactions could potentially have many
important pathological outcomes.
The authors would like to thank Allen Kane for assistance
with illustrations, and Scott McNeil and Jennifer Hall for helpful
This project has been funded in whole or in part with federal
funds from the National Cancer Institute, National Institutes
of Health, under contract N01-CO-12400. The content of this
publication does not necessarily reflect the views or policies of the
Department of Health and Human Services, nor does mention of
trade names, commercial products, or organizations imply endorse-
ment by the U.S. government.
1. Stern ST, Zolnik BS, McLeland CB, Clogston J, Zheng J, McNeil SE. Induction of
autophagy in porcine kidney cells by quantum dots: A common cellular response to nano-
materials? Toxicol Sci 2008; 106:140-52.
2. Yoshimori T. Autophagy: A regulated bulk degradation process inside cells. Biochem
Biophys Res Commun 2004; 313: 453-8.
3. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 2005;
4. Chen Y, Yang L, Feng C, Wen L-P. Nano neodymium oxide induces massive vacuolization
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5. Seleverstov O, Zabirnyk O, Zscharnack M, Bulavina L, Nowicki M, Heinrich JM,
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in children and young adults above identified dramatic particulate
deposition in olfactory bulb neurons from individuals in high pollu-
tion areas.41 Furthermore, Oberdörster et al. (2004) demonstrate
that 13C labeled carbon nanoparticles concentrate in the olfactory
bulb and CNS following inhalation exposure in rats,47 supporting
a role for both olfactory and systemic translocation of carbon-based
combustion-derived nanoparticles into the CNS. The studies above
describing particulate laden intralumenal erythrocytes in frontal and
trigeminal ganglia capillaries, and damaged blood brain barrier,41
would also support direct CNS uptake of systemic particles through
the damaged endothelium. Future studies should examine the poten-
tial role of pollution-derived nanoparticles in the etiology of AD and
PD by way of an autophagy dysfunction mechanism.
Our laboratory is currently involved in screening nanomaterials for
interaction with the autophagy system, with the intent of identifying
a structure-activity-relationship and delineating the mechanisms
by which this interaction occurs. It is important to note that only
a small percentage of the ambient and engineered nanomaterials
studied in our laboratory thus far have been shown to influence
autophagy (unpublished data). However, there is great variety within
the subset of nanomaterials that do influence autophagy, the only
commonality appearing to be size on the nanoscale. This great
variety, evaluated in such diverse cell types, would suggest that this
Figure 1. Schematic representation of nanomaterial-autophagy interaction in neurodegerative disease. In this hypothetical scheme, pollution-derived nano-
particles enter the CNS by neuronal transport or via the systemic circulation. Low-level acute nanoparticle exposure activates autophagy, resulting in particle
clearance. In a chronic or high-level exposure scenario, the particles have toxic effects on neurons, through generation of oxidative stress and inflamma-
tion, or by disruption of homeostatic autophagy. Impairment of autophagy results in accumulation of toxic protein aggregates, neuronal loss, and ultimately
©2008 Landes Bioscience. Do not distribute.
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