Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.

1. Drosophila models of inherited peripheral
neuropathy

2. ¿Why Drosophila?
Practical reasons: fast, cheap and small
Relevance: high similarity to other animals
Experimental advantages: techniques and resources
¿Why Drosophila?
Practical reasons: fast, cheap and small
Relevance: high similarity to other animals
Experimental advantages: techniques and resources
COMPLEXITY
ECONOMY

5. Nobel Prize in Medicine in 1946
Herman Joseph Muller “For his discovery that X-rays cause mutations”.
Nobel Prize in Medicine in 1946
Herman Joseph Muller “For his discovery that X-rays cause mutations”.
Nobel Prize in Medicine in 1995
Christiane Nusslein-Volhardt, Eric Wieschauss and Ed Lewis. “for their studies on
the genetic control of early embryonic development”.
Nobel Prize in Medicine in 1995
Christiane Nusslein-Volhardt, Eric Wieschauss and Ed Lewis. “for their studies on
the genetic control of early embryonic development”.
Nobel Prize in Medicine in 2011
Bruce A. Beutler and Jules A. Hoffmann (innate immune system) and Ralph M.
Steinman (discovery of the dendritic cell and its role in adaptative immunity)
Nobel Prize in Medicine in 2011
Bruce A. Beutler and Jules A. Hoffmann (innate immune system) and Ralph M.
Steinman (discovery of the dendritic cell and its role in adaptative immunity)
Nobel Prize in Medicine in 1933
Thomas Hunt Morgan “for his discoveries on the role of chromosomes in heredity”.
Nobel Prize in Medicine in 1933
Thomas Hunt Morgan “for his discoveries on the role of chromosomes in heredity”.

6. Drosophila models of neurodegenerationDrosophila models of neurodegeneration

7. Human Gene Main Pathology Drosophila Gene
GDAP1 CMT4A, CMT2K, AR-CMT2K Gdap1
MFN2 CMT2A2 Mfn
OPA1 Optic atrophy opa1-like
DRP1 Lethal encephalopathy Drp1
FIS1 Fis1
PINK1 Autosomal Recessive Parkinsonism Pink1
parkin Autosomal Recessive Parkinsonism Parkin
Mitochondrial dynamics and neurodegenerationMitochondrial dynamics and neurodegeneration

8. TransgenicsTransgenics

9. Random insertions
Targeted landing
Genome editing

10. Gal4
Binary Gal4-UAS system: expression, RNAiBinary Gal4-UAS system: expression, RNAi
UAS
elav UAS GDAP1Gal4
X
Gal4 is a transcription factor from
Saccharomyces cerevisiaeelav
MHC
MHC UAS GDAP1Gal4

11. DNA clones(>1.000.000) and cell lines (136)DNA clones(>1.000.000) and cell lines (136)Drosophila stocks (over 45.000)Drosophila stocks (over 45.000)
Drosophila Genome Project, Drosophila Heterochromatin Genome Project, modENCODE Project,
Gene Expression Patterns, Gene Disruption Project (14000 lines), DNAs (libraries, cDNAs)
Drosophila Genome Project, Drosophila Heterochromatin Genome Project, modENCODE Project,
Gene Expression Patterns, Gene Disruption Project (14000 lines), DNAs (libraries, cDNAs)
TRiP lines: 6.000 RNAi linesTRiP lines: 6.000 RNAi lines GD library, KK library, VT Gal4 libraryGD library, KK library, VT Gal4 library

18. Age
1 week
(young flies)
5 weeks
(old flies)
NEURODEGENERATION
Tissues
eye muscle
Genotypes
Normal expression Over-expression RNAi

19. Altering levels of Gdap1 causes neuronal death
(1 week)
RNAiControl Overexpression
4
2 1
3
5
6
7
4
2
1
3
5
6
4
2
1
3
5
6
(5 weeks)
4
2 1
3
5
6
7
4
2 13
5
6 4
2
1
3
5
RNAiControl Overexpression
RNAi + human GDAP1
4
2
1
3
5
6
7
4
2
1
3
5
6
7
RNAi + human GDAP1

20. Gdap1 altered levels affect lamina stucture
Control Over-expression RNAi

21. Gdap1 affects mitochondrial morphology
1 week
Control
RNAi
Over-expression
5 weeks

22. 0
5
10
15
(AU)
***
*
0
5
10
15 **
*
FREE GSH LEVELS RATIO GSH/GSSG
0
50
100
150
REL.FLUO/PROT.CONTENT
*
***
GLUTATHIONYLATION
NITROSYLATION
0
1
2
3
4
(AU)
**
***
SOD2DCF
C O K C O K
C O K C O K
1 week 5 weeks
1 week 5 weeks
1 week 5 weeks 1 week 5 weeks
control
over-expression
knock down

23. THE CHALLENGE FOR THE FUTURE:
TRANSLATION OF FLY STUDIES TO THE CLINICAL PRACTICE
THROUGH IDENTIFICATION OF NEW BIOMARKERS AND
TREATMENTS.

24. GDAP1:CMT4A, CMT2K,
CMTA
GENETIC HETEROGENEITY
TISSUE-SPECIFICITY
LEVELS OF EXPRESSION
PHYSIOLOGICAL FEED-BACK
PHYSIOLOGICAL CONTEXT

25. Humanised flies for biomarker determination and drug screening

26. Laboratory of Developmental Biology and
Neuromuscular Disease Models