4 research outputs found
Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons
Fibrillar αSynuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson’s disease (PD). Multiplications of the αSynuclein gene, as well as point mutations cause familial PD. However, the exact role of αSynuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing αSynuclein mediates neurotoxicity. To investigate the impact of αSynuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant αSynuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of αSynuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the αSynuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric αSynuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of αSynuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of αSynuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients
Efficient Gene Therapy for Parkinson's Disease Using Astrocytes as Hosts for Localized Neurotrophic Factor Delivery
Current gene therapy approaches for Parkinson’s
disease
(PD) deliver neurotrophic factors like glial cell
line-derived neurotrophic factor (GDNF) or neurturin
via neuronal transgene expression. Since these potent
signaling-inducing neurotrophic factors can be distributed
through long-distance neuronal projections to
unaffected brain sites, this mode of delivery may eventually
cause side effects. To explore a localized and
thus potentially safer alternative for gene therapy of
PD, we expressed GDNF exclusively in astrocytes and
evaluated the efficacy of this approach in the mouse
1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP)
and rat 6-
hydroxy-dopamine (6-OHDA) models of PD.
In terms of protection of dopaminergic cell bodies and
projections, dopamine (DA) synthesis and behaviour,
astrocyte-
derived GDNF demonstrated the same efficacy
as neuron-derived GDNF. In terms of safety, unilateral
striatal GDNF expression in astrocytes did not result in
delivery of bio-active GDNF to the contralateral hemispheres
(potential off-target sites) as happened when
GDNF was expressed in neurons. Thus, astrocytic GDNF
expression represents a localized but efficient alternative
to current gene therapeutic strategies for the treatment
of PD, especially if viral vectors with enhanced tissue
penetration
are considered. Astrocytic neurotrophic
factor
expression may open new venues for neurotrophic
factor-based gene therapy targeting severe diseases of
the brain.peerReviewe