Biology Reference
In-Depth Information
DA is synthesized in the cytosol and packaged into synaptic vesicles by
the conserved vesicular monoamine transporter (VMAT). A consensus appears
to be emerging that increased production of cytoplasmic DA, by transgenic
expression of the rate limiting enzyme TH (encoded by the
pale
gene in Dro-
sophila) or by downregulation of
VMAT
, enhances toxicity of
-synuclein
or
mutant human
parkin
models (Park
et al.
, 2007; Sang
et al.
, 2007). In contrast,
depletion of cytosolic DA by RNAi of
to
accelerate DA packaging was protective in these models. Furthermore, parallel
studies have revealed potential significance for DA metabolism in sporadic PD
since loss of Drosophila
pale
or overexpression of
VMAT
function confers sensitivity to paraquat and the
mitochondrial toxin rotenone (Lawal
VMAT
et al.
, 2010), whereas overexpression of
VMAT
or downregulation of
pale
is protective against rotenone toxicity
(Bayersdorfer
, 2010). Interestingly, VMAT expression
does not protect against paraquat toxicity suggesting the principal insult from
paraquat and rotenone may be different (Lawal
et al.
, 2010; Lawal
et al.
, 2010). The overall findings
from these studies suggest that promoting the packaging of cytoplasmic DA into
vesicles reduces toxicity; however, contradictory findings results have also been
reported. One study characterizing of the effects of various genetic and pharma-
cologic manipulation of DA upon a paraquat and hydrogen peroxide-induced
neurotoxicity described a complex effect of increasing and decreasing the pro-
duction of DA and its cofactor tetrahydrobiopterin on Drosophila survival and
DA neurodegeneration (Chaudhuri
et al.
, 2007). Again, some differences were
observed between effects on paraquat versus hydrogen peroxide treatment, which
may reflect different toxic mechanisms. While some of these details await
verification, the data are consistent with the notion that the presence of DA
may impact on the burden of toxicity contributing to cell type specificity.
A final link to novel therapeutic strategies in which Drosophila models
have contributed involves members of the histone deacetylase (HDAC) protein
family. First, numerous studies of yeast and metazoan Sir2 homologs indicate that
they play a role in multiple cellular processes including cell survival and promo-
tion of organismal life span (Blander and Guarente, 2004). A number of chemi-
cal inhibitors were identified that selectively inhibit yeast Sir2 activity (Outeiro
et al.
et al.
, 2007), and were found to decrease the number but increase the size of
-synuclein aggregates. Administration of the Sir2 chemical
inhibitors to
-synuclein-expressing flies was shown to prevent the toxicity of
-synuclein
in a dose-dependent manner (Outeiro
, 2007). These findings are particularly
compelling since other HDAC inhibitors have been shown to ameliorate ex-
panded polyglutamine-induced toxicity (Steffan
et al.
, 2001). The mechanisms
by which inhibiting HDAC activity relieves toxicity in these models of neuro-
degeneration remain unclear. However, universal HDAC inhibition may not be
a sensible strategy. In contrast to these results, genetic ablation of Drosophila
HDAC6
et al.
was found to exacerbate
-synuclein neurotoxicity (Du
et al.
, 2010).
