Neurodegeneración y neuroprotección en el sistema nervioso adulto

Abril 28, 2011. F. Pfizer/ISCiii. Hotel Eurostar, Madrid
Grandes retos actuales en la Investigación Biomédica e instrumentos para el desarrollo de una investigación
de vanguardia en España
Neurodegeneración y neuroprotección en el sistema nervioso adulto
José López-Barneo
Instituto de Biomedicina de Sevilla (IBiS)
Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Sevilla
Human brain
Neuronal networks
Neurodegeneration: Progressive loss of neurons without an apparent cause (traumatic,
infectious or ischemic) normally associated with age
Enfermedades neurodegenerativas más frecuentes
Enfermedad de Alzheimer y otras demencias
Enfermedad de Parkinson
Otras (Coreas, Ataxias, Esclerosis lateral amiotrófica…)
(Pérdida progresiva de neuronas y atrofia cerebral. Alteración de las
funciones motoras, sensoriales, emocionales y cognitivas)
Neurodegeneración: reto biomédico del siglo XXI
(Problemas muy frecuentes. Curso crónico e invalidante. Alto coste
para las personas, el enfermo y sus familiares, social y sanitario)
Neuronal loss in Parkinson’s disease
D. Tremor-rigidity-bradykinesia
(Shaking palsy)
Cuerpos de Lewy
Dauer et al. Neuron (2003)
Grandes retos en la investigación sobre enfermedades
neurodegenerativas
- Comprender la etiopatogenia (Pathogenesis)
factores etiológicos y nuevas dianas farmacológicas
modelos que recapitulen la enfermedad
- Terapias avanzadas (Advanced therapies)
Pathogenesis of Parkinson’s disease
Feany, New England Journal of Medicine (2004)
Mitochondrial complex II (Succinate dehydrogenase)
SDHA
SDHB
SDHC
SDHD
Hederstedt, Science (2003)
Selective dopaminergic neuronal death in SDHD KO mouse
WT
SNc
VTA
SDHD-/-
Patient-specific induced pluripotent stem cells and dopaminergic neurons
CIBERNED’s “Parkinson Cooperative Project”
Cundiff and Anderson, Current Opinion in Genetics and Development ( 2011)
Local and retrograde signalling of neurotrophic factors
b
Soma
Axon
terminals
c
Axons
(pre)
Dendrite
(post)
Sweifel et al., Nature Reviews Neuroscience ( 2005)
a
Effect of trophic factors on the nigrostriatal pathway
Str
SN
Toledo-Aral et al., unpublished
The glial cell line-derived neurotrophic factor (GDNF) is a potent
dopaminergic neuroprotective agent
Embryonic mesencephalic neurons
+ GDNF
- GDNF
Lin et al., Science (1993)
Conditional GDNF “knock out” mouse
Birth
2m
3m
TM Protein
DNA, H
Pascual et al., Nature Neuroscience (2008)
5m
9m
RNA
Histology
Striatal DNA
Death of mesencephalic dopaminergic neurons in the adult
conditional GDNF knock out mice
Wild type
GDNF -/-
SN
VTA
Pascual et al., Nature Neuroscience (2008)
Adult conditional GDNF knock out mice
GDNFKO
WT
Hippocampus
Pascual et al., Nature Neuroscience, 2008
Cortex
Arcuate N.
Selective GDNF expression in the striatal connectome
GDNF+ (<3%)
Synchronized PV+ striatal
“fast spiking” interneurons
Striatal neuronal output (~90%)
Humphries et al., PLoS Computer Biology (2010)
The human carotid body; an abundant source of GDNF
Weir, López-Barneo, Buckler & Archer, New England Journal of Medicine (2005)
Villadiego et al., Journal of Neuroscience (2005)
Neuroprotective effect of intrastriatal CB transplantation
Autotransplantation of CB cell aggregates in PD patients
A
C
B
Arjona et al., Neurosurgery (2003)
Clinical and neurochemical outcomes of CB transplanted PD patients
A
B
160
3 years: 15% to 48% (n=3)
Blinded UPDRS III score in “off”
140
140
120
120
1
A1
2
A2
100
100
3
A3
4
A4
5
A5
6
A6
80
80
60
60
40
40
20
20
Pre
6
12
18
24
months
Arjona et al., Neurosurgery (2003)
Mínguez-Castellanos et al., Journal of Neurology, Neurosurgery & Psychiatry (2007)
PET, baseline and 12 months
Neurogenic niches in the adult central and peripheral nervous system
Kokovay and Temple, Cell (2007)
Identification of stem/progenitor cells in the adult carotid body
(neurosphere assay)
bleb
b
c
core
50 µm
Single deposition experiment
50 µm
Pardal et al., Cell (2007)
Mouse carotid body neurospheres
Neurospheres
Carotid body
TH
TH / DAPI
Intrastriatal grafts
Neurospheres
Lopez-Barneo et al., unpublished
Carotid body
GDNF
Neurodegeneración y neuroprotección en el sistema nervioso adulto