4 YEAR PhD IN NEUROSCIENCE
THE MOLECULAR NEUROPATHOBIOLOGY LABORATORY
The maintenance of the unique morphology of a neuron, which is based on the strict polarisation into axonal and dendritic compartments, is crucial for its functions and survival. Compartmental identity is ensured by a network of axonal transport pathways allowing efficient communication over long distances. Axonal transport constitutes the backbone of long-distance crosstalk in neurons, functionally connecting peripheral compartments, such as synapses, with events occurring in the soma and vice versa.
The research efforts of our laboratory are focused on proving the central hypothesis that the impairment of the selectivity and/or the efficiency of long-range communication in neurons caused by defects in axonal transport and vesicular traffic constitutes a major pathogenic mechanism in neurodegenerative disorders. We will address this challenge by integrating the molecular and cellular analysis of axonal transport together with the study of this process in vivo. We are in the process of assembling a functional map of the organelles responsible for the axonal transport and for sorting of neurotrophin receptor complexes. Furthermore, we are identifying the key determinants for their regulation and signalling.
Currently our available projects focus on addressing the following questions:
· How does the composition of axonal retrograde transport carriers change during their progression along axons? Does their composition vary in neurons with similar morphology, but affected by different diseases?
· Which factors are essential for the biogenesis and axonal transport of these axonal carriers?
· How do Rab GTPases, in particular Rab7 and Rab10, control axonal retrograde transport and transcytosis? How are their activities co-regulated?
· Are targeted screens in embryonic stem (ES) cell-derived motor neurons exploitable to improve our understanding of axonal transport and for the identification of novel therapies for the treatment of neurodegenerative diseases?
Restani L, Giribaldi F, Manich M, Bercsenyi K, Menendez G, Rossetto O, Caleo M and Schiavo G (2012) Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog 8, e1003087.
Rishal I, Kam N, Shinder V, Fisher EMC, Schiavo G and Fainzilber M (2012) Motor driven intracellular length sensing in neurons. Cell Reports 1, 1-9.
Cesca F et al. (2012) Kidins220/ARMS Mediates the Integration of the Neurotrophin and VEGF Pathways in Cardiovascular and Nervous System Development. Cell Death Differ 19, 194-208.
Bilsland L, Sahai E, Kelly G, Golding M, Greensmith L and Schiavo G (2010) Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A 107, 20523-20528.
Schiavo G, Greensmith L, Hafezparast M and Fisher EMC (2013) Cytoplasmic dynein heavy chain: the servant of many masters. Trends Neurosci, in press.
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