Biology Reference
In-Depth Information
-synuclein modification and
aggregate formation to DA neuron loss, investigators analyzed the effects of
posttranslational modifications of
To explore further the relationship of
-synuclein on aggregate formation and neu-
ronal viability. Previous work showed that
-synuclein is extensively phosphory-
lated in the brains of PD individuals, particularly at serine residue 129, and that
the phosphorylation status of
-synuclein influences its propensity to form
aggregates
in vitro
(Fujiwara
et al.
, 2002; Okochi
et al.
, 2000). Interestingly, the
phosphorylation of
-synuclein at Ser129 appears to be conserved in Drosophila
(Takahashi
, 2003). To explore the consequence of Ser129 phosphorylation
on aggregate formation and neuronal integrity, Chen and Feany generated
mutationally altered
et al.
-synuclein transgenic constructs; a Ser129 to Ala
(S129A) mutation to prevent phosphorylation and a Ser129 to Asp (S129D)
mutation to mimic the phosphorylated state (Chen and Feany, 2005). The
extent and timing of pathology of these transgenic constructs was compared
with WT
-synuclein. Expression of the S129D construct accelerated the onset
of DA neuron loss, increased retinal degeneration, and reduced the amount of
-
synuclein in aggregates relative to WT
-synuclein. By contrast, expression of
the S129A construct resulted in reduced DA neuron loss and increased the total
load of aggregated
-synuclein protein. These results suggest that phosphoryla-
tion of Ser129 could maintain
-synuclein in a nonaggregated but more toxic
conformation. In contrast, recent analysis of a putative phosphorylation at Y125
suggests that this modification led to a decrease in soluble
-synuclein oligomers
and was less toxic than WT or S129 phosphorylation (Chen
et al.
, 2009).
Together these findings suggest that
-synuclein's toxicity, and likely its normal
function, may be modulated by phosphorylation and imply the presence of
specific kinases.
Overall,
-synuclein
aggregates correlates with decreased cellular toxicity, implying that Lewy
body formation is a neuronal detoxification response and has significant
implications for potential therapeutic approaches. The finding that phosphor-
ylation enhances
these findings
suggest
that an increase in
-synuclein toxicity suggests that the kinases responsible for
phosphorylation might represent therapeutic targets for small-molecule inhi-
bitors. It will be important to identify these kinases and characterize their
activity to know if their inhibition may be a viable therapy. More crucially,
the evidence that inclusion formation is protective challenges current thera-
peutic strategies to prevent inclusion formation which may even augment
disease progression. While the precise mechanisms of toxicity remain unclear,
this evidence lends support to the early findings that administration of the
HSP70-inducing geldanamycin is able to suppress
-synuclein toxicity,
suggests this avenue as a possible treatment strategy for PD (Auluck and
Bonini, 2002).
