<p class="first" id="P2">DJ-1 is a redox-sensitive protein with several putative functions
important in mitochondrial
physiology, protein transcription, proteasome regulation, and chaperone activity.
High levels of DJ-1 immunoreactivity are reported in astrocytes surrounding pathology
associated with idiopathic Parkinson’s disease, possibly reflecting the glial response
to oxidative damage. Previous studies showed that astrocytic over-expression of DJ-1
<i>in vitro</i> prevented oxidative stress and mitochondrial dysfunction in primary
neurons. Based
on these observations, we developed a pseudotyped lentiviral gene transfer vector
with specific tropism for CNS astrocytes
<i>in vivo</i> to overexpress human DJ-1 protein in astroglial cells. Following vector
delivery
to the substantia nigra and striatum of adult Lewis rats, the DJ-1 transgene was expressed
robustly and specifically within astrocytes. There was no observable transgene expression
in neurons or other glial cell types. Three weeks after vector infusion, animals were
exposed to rotenone to induce Parkinson’s disease-like pathology, including loss of
dopaminergic neurons, accumulation of endogenous α-synuclein, and neuroinflammation.
Animals over-expressing hDJ-1 in astrocytes were protected from rotenone-induced neurodegeneration,
and displayed a marked reduction in neuronal oxidative stress and microglial activation.
In addition, α-synuclein accumulation and phosphorylation were decreased within substantia
nigra dopaminergic neurons in DJ-1–transduced animals, and expression of LAMP-2A,
a marker of chaperone mediated autophagy, was increased. Together, these data indicate
that astrocyte-specific overexpression of hDJ-1 protects neighboring neurons against
multiple pathologic features of Parkinson’s disease and provides the first direct
evidence
<i>in vivo</i> of a cell non-autonomous neuroprotective function of astroglial DJ-1.
</p>