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This site is dedicated to scientific community working on ALS. Our aim is to optimize researchers time and efforts by providing updated, well organized information on novel findings, available resources and research support.
AriSLA - The Foundation for research on ALS - has been set up to make ALS research investments more effective and efficient, to speed up the clinical research impact e and to provide patients with better care, improved conditions and life expectancy. Its aim is to boost Italian excellencies in basic, clinical and technological research. The Foundation founders are Fondazione Cariplo, Fondazione Telethon, Fondazione Vialli and Mauro and AISLA.

 

 

Curriculum in Neuroscience and Experimental Neurology - Final Course Programme

The neuronal soma: a key functional component of the axon (paradox intended)" 

San Raffaele Scientific Institute, Milan, Italy

14 and 15 June 2018

Organizers: G. Consalez (San Raffaele Scientific Institute)

F. Casoni (UniSR)

G. Viero (CNR, Trento)

M. D'Antonio, P. D'Adamo (San Raffaele Scientific Institute) 

Foreword

The axon is not a translationally inert territory

While the majority of neuronal proteins are manufactured in the endoplasmic reticulum and in cytosolic polysomes of the neuronal cell body, many proteins affecting synaptic plasticity are synthesized in dendrites. Conversely, the axon has long been viewed as a passive transmitter of information relying, for protein synthesis and homeostasis, on bidirectional vesicular traffic, to and from the soma. However, an average pyramidal neuron's axonal volume can reach 1000 times the volume of its cell body. More importantly, increasing evidence emphasizes the role of localized protein synthesis, translational control, and locally regulated metabolism in axons. Sustained local translation in distal axons is key to neuronal survival. Decreased translation of mRNAs trapped inpathological aggregates might damage distal axons, causing the death of postmitotic neurons.Local mRNA translation is required for presynaptic maturation and plasticity. Thus, it is likely that sustained local translation in the presynaptic terminal be required for synaptic maintenance in adult mice. In fact translational activity is enhanced by extrinsic cues (BDNF, netrins and semaphorins),by mTORC1-induced 4E-BP phosphorylation, or by decreasing eIF2a phosphorylation. In mammals, local translation has been observed in the axon of cultured embryonic neurons, in embryonic peripheral sensory axons, in the axonal initial segment of adult CNS neurons, and in mature PNS axons, with polysomes located close to the plasma membrane. Axons, including adultones, contain noncoding RNAs, including miRNA, and transport RNAs. Moreover, several messenger RNAs are targeted to the axon: for example, the 3'UTR of the importin β1 mRNA contains an axon-targeting signal, and transcript localization to the axon is important for efficient regeneration.

The axon and motor neuron disorders.

While all genes mutated in isolated or familial cases of amyotrophic lateral sclerosis (ALS) are ubiquitously expressed, neurodegeneration mainly affects long-range (sometimes meter-long) projection neurons - definitely the longest motor axons of the human body. The upper and lower motor neurons, which are prone to degeneration in ALS patients, might be particularly sensitive to pathological messenger ribonucleoprotein aggregates. In ALS, presynaptic and axonal damageprecedes the demise of the neuronal cell body. A sudden decline in the level of synaptic proteins precedes defective synaptic function and neuronal loss, suggesting that defective maintenance of the synaptic proteome could be an underlying cause of neurodegeneration. Thus, it is likely thatsustained local translation in the presynaptic terminal be required for synaptic maintenance in adult mice. Similar principles are predicted to apply to other neurodegenerative disorders affecting long range projection neurons.In this course, we plan to discuss some aspects of axonal biology, metabolism and transport, and their potential relevance for neurodegenerative disorders. 

 

 

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