[Todos] Seminarios conjuntos DFBMC-IFIByNE- Prof.Dr. Jorge E. Moreira, RECORDATORIO

[Paula Felman]

Seminario 28 de agosto. Aula LFBM, 13:00 hs

Title: “Experimental Parkinson's disease: MPP+ and mutant
-synucleins affect axonal transport and synaptic activity in the
squid giant synaptic system.”

Prof.Dr. Jorge E. Moreira,
Department of Cell and Molecular Biology
University of São Paulo School of Medicine at Ribeirão Preto
Ave. Bandeirantes 3900
14049-900 Ribeirão Preto, São Paulo, Brasil
55(16)3602-3284/3216
FAX: 55(16) 3633-1786

Abstract: Intracellular aggregates of alpha-synuclein known as Lewy bodies
(LB) are a pathological hallmark of Parkinson's disease (PD). Further,
point mutations in alpha-synuclein are linked to some familial Parkinson's
(fPD) cases. Recombinant alpha-synucleins allowed us to evaluate changes
in squid axonal transport associated with both fPD mutant alpha-synucleins
and LB made from wild type (WT) alpha-synucleins. Mutant alpha-synucleins
(A30P and A53T) increased dynein-based retrograde transport (RT), reduced
kinesin-based anterograde transport (AT), and altered dynein intermediate
chain (DIC) phosphorylation. These changes were comparable to those
produced by treating squid axoplasm with active Protein Kinase C (PKC)
catalytic subunits and Src family tyrosine kinases. Inhibitors of PKCs or
the tyrosine kinases could block mutant alpha-synuclein effects on RT.
This indicates that a novel PKC-dependent pathway exists for activating RT
via mutant alpha-synucleins and is consistent with reports of altered
protein phosphorylation in PD. Preliminary studies indicate that LB
filaments affect axonal transport similarly and suggest a common
pathogenic pathway in fPD and sporadic PD. Altered trafficking of
organelles in axonal transport can affect trophic interactions and
synaptic function, leading to synaptic loss and neuronal death. Given the
role of alpha-synucleins in fPD and formation of LB in sporadic PD, these
findings suggest a novel pathogenic mechanism in PD: We propose that
presence of mutant alpha-synucleins or LB alter regulatory pathways
critical for maintaining the normal balance between AT and RT in
dopaminergic neurons. We also examined the toxic metabolite of MPTP
(1-metil-4-fenil-1,2,3,6-tetrahidropiridina), MPP+, that affects FAT just
as fPD alpha-synucleins and LB filaments do. Giant squid synapses injected
with either MPP+ or A30P mutant alpha-synuclein exhibiting a failure of
neurotransmission were processed for EM morphometry along with paired
synapses injected with WT alpha-synuclein as described previously.
Proportional changes were noted in total vesicles, docked vesicles and
clathrin-coated vesicles per active zone. Both failure of
neurotransmission and the absence of synaptic vesicles are consistent with
an activation of RT that depletes presynaptic terminals and compromises
neuronal function. Taken together, these results suggest a novel
pathogenic mechanism for loss of nigral dopaminergic neurons in PD. We
propose that pathogenic forms of alpha-synuclein alter normal regulation
of FAT and compromise neuronal function. Normal pathways for regulating
FAT through one or more PKC isoforms may be altered by increases in local
PKC activities and result in a premature return of vesicles to the cell
body. This reduces the availability of synaptic components for
neurotransmitter release as well as affecting return of neurotrophins. As
a result, synaptic function of dopaminergic neurons is reduced and
eventually lost, triggering the dying back neuropathy and eventual death
of affected neurons. We have named such dying-back phenomena due to
alterations in vesicular trafficking a dysferopathy, from the Greek fero:
to carry or to transport. The possibility that the dying-back phenomenon
due to a dysferopathy is not a sui generis case for the MPTP Parkinson's,
but rather a possible mechanism for other thalamocortical dysrhythmias,
has wide implications both in neurological as well as psychiatric
conditions.
Host: Francisco Urbano/Osvaldo Uchitel