Peer Review of Synergistic Effects of Pesticides and Metals in Parkinson's

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Synergistic Effects of Pesticides and Metals on Fibrillation of α-Synuclein:
Implications for Parkinson’s Disease
Vladimir N. Uversky, Jie Li, Kiowa Bower, Anthony L. Fink*
Dept of Chem and BioChem, Univ. of California, Santa Cruz, CA 95064
A Peer Review by
Arloe P. Fontenot

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Synergistic Effects of Pesticides and Metals on Fibrillation of α-
Synuclein: Implications for Parkinson’s Disease
Introduction
-alpha-Synuclein, is a synuclein protein of unknown function found primarily
in neural tissues; it is seen mainly in the presynaptic terminals.
-a-Synuclein is expressed predominantly in the neocortex, hippocampus,
substantia nigra, thalamus, and cerebellum. Although primarily a neuronal
protein; this protein can also be found in glial cells, those which bind and
provide structure for the neuronal cells.
-Lewy bodies are abnormal, intraneural cytoplasmic inclusions composed of
filaments of a-synuclein that radiate out from a central core. Morphologically,
they appear as either classical (brain stem) or cortical.
-The main disease associated with the presence of Lewy bodies is Parkinson’s
Disease, of which its cause is still unknown.

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Introduction
-alpha-Synuclein is an abundant brain protein consisting of 140 amino acids
and of relatively unknown function, and belongs to a class of proteins known to
be natively unfolded; i.e its purified structure is substantially disordered at
neutral pH.
-Fibrils, or clusters, of a-synuclein have been found and reported from
individuals with Lewy body diseases, as well as Lewy bodies sequestered in
vitro.
-The authors recently reported preliminary studies which indicated certain
pesticides and metals could accelerate the formation of a-synuclein fibrils,
acting individually or synergistically. Both of these agents induce
conformational change in a-synuclein; which is likely a critical precursor to
association and fibrillation.
-These observations may serve to suggest an underlying molecular basis for PD
and other Lewy body diseases.

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Introduction
Lewy Bodies
Small, dense deposits, termed Lewy
bodies or Lewy neurites, stud the brains
of patients with Parkinson's disease. The
three sections of brain tissue shown
above depict how the protein, alpha-
synuclein (stained brown), packs these
deposits. This finding, and others, leads
many scientists to believe that alpha-
synuclein plays a key role in Parkinson's
disease. Researchers are now searching
for ways to stop their negative actions
and hopefully aid patients in the future.
Reprinted by permission from Nature, M.G. Spillantini et al.,
388:839 (1997)
© 2001 MACMILLAN MAGAZINES LTD.

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Introduction
Parkinson’s Disease…and a possible
mechanism
Description: The motor defects of Parkinson's disease are related to
the loss of dopaminergic neurons in specific brain regions.
Examination of these neurons in diseased tissue has revealed the
presence of Lewy bodies, dense aggregates that include the
protein alpha-synuclein. A genetic basis for most cases of
Parkinson's disease has not yet been identified, but mutations in
alpha-synuclein have been associated with at least one rare form
of the disease, and mutations in another protein, the parkin
gene, are associated with another inherited form of Parkinson's
disease. Parkin is found in Lewy bodies along with alpha-
synuclein and the parkin protein is an enzyme, an E3
ubiquitin ligase. This ligase tags specific proteins in normal
cells with ubiquitin, targeting them for destruction in the
proteosome (see Proteosome pathway). One of the proteins
that parkin normally targets for destruction is a specific O-
glycosylated form of alpha-synuclein. Failure of parkin-
mediated degradation of alpha-synuclein may be a key factor
leading to the death of dopaminergic neurons. Another substrate
of parkin is a GPCR-like protein called Pael-R that accumulates in
the ER of affected cells and may cause neuronal cell death. The
involvement of Parkin and alpha-synuclein mutations in genetic
forms of Parkinson's suggest that failure of ubiquitination and
protein degradation may be causative in other forms of
Parkinson's. Questions remaining include the cause of the lack of
effective ubiquitination in individuals lacking obvious genetic
defects in this pathway and how to use this knowledge of
ubiquitination and protein degradation in Parkinson's disease to
identify therapeutic strategies.
Contributors: Glenn Croston, PhD.
References: Shimura, H. et al. (2001) Ubiquitination of a New Form
of alpha-Synuclein by Parkin from Human Brain: Implications for
Parkinson's disease. Science 293 (5528) 263-269

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Synergistic Effects of Pesticides and Metals on Fibrillation of α-Synuclein: Implications for Parkinson’s Disease
Materials, Methods, & Experimental Design
*a-Synuclein was expressed and prepared based on an earlier experiment by the authors

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Results – a-Synuclein fibrillation in presence of pesticides

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Results – “Dose-Dependence” a-Synuclein fibrillation in the presence of dieldrin

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Results – The [AlCl3] required to accelerate a-synuclein decreases at higher [a-synuclein]

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Results – Metal ion and pesticide-induced conformational changes in a-synuclein

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Results – Synergistic effects between pesticide (DDC) and metal (AlCl3)

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Discussion
-Of the pesticides the authors examined, those that showed the most significant accelerating effects were rotenone, DDT,
2.4-D, dieldrin, diethyldithiocarbamate, paraquat, maneb, trifluralin, parathion, and imidazoldinethione.
-MPP+, the active metabolite of MPTP that causes PD-like symptoms in humans and primates by acts to inhibit Complex I
of the mitochondria had no significant effect on the kinetics (fibrillation) of a-synuclein. However, rotenone, which
also inhibits Complex I of the mitochondria, accelerated a-synuclein fibrillation.
-Pesticides in general showed increasing rates of fibrillation with increasing concentration of pesticide.
-In terms of metals, trivalent metals coupled with low pH were most effective at stimulating fibrillation. The most effective
ions were Al3+, Fe3+, Co3+, Cd2+, Mn2+, Cu2+, Co2+, respectively. There was a good correlation between charge
density and effectiveness in stimulating a-synuclein fibrillation.
-The results were consistent with a model in which both the cations (above) and pesticides interact with a-synuclein to
create conformational change of the protein to a partially-folded state with a high propensity to aggregate.
-Also noted that increasing hydrophobicity of pesticides is an important factor in stimulating aggregation, by binding to the
partially-folded intermediate conformation, thereby increasing he population of the intermediate.

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Discussion
Thus, environmental factors that
stimulate the aggregation of
a-synuclein do so by binding to
and increasing the concentration of
the partially-folded intermediate
conformation that lead to
aggregation.

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Comments and Criticism
-results section was only partial for all pesticides tested
-only results for a single metal’s effects was shown
-preparation of the paper’s main target (a-synuclein) was left out of the Materials and Methods
prep session, though mentioned in a previous paper. Would have been good to include anyway.
-overall, a good paper in my opinion, illustrating the effects of pesticides and certain cationic
metals on the formation of Lewy bodies
Thanks!

Peer Review of Synergistic Effects of Pesticides and Metals in Parkinson's

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