Biology Reference
In-Depth Information
different motor proteins, different scaffold proteins linking to these motors, and
different regulatory mechanisms. Some proteins can also be synthesized locally
within axons. The combined effect is that some proteins are completely dispens-
able for long-term axon survival, while a failure to deliver others kills axons in
hours.
Molecular genetics gives us some insight into what is most essential.
Spontaneous null mutations in man or model organisms and targeted gene
disruptions help to identify proteins that axons cannot live without. Among
them are many components of the axonal transport machinery itself, some
mitochondrial proteins, adhesion molecules, and mediators of the ubiquitin
proteasome system and autophagy. However, a surprising array of axonal proteins
are not essential for survival. These include highly abundant axonal proteins
such as neurofilament subunits, several disease-associated proteins, and key
mediators of axon and synapse function. Some axons can even survive days
without mitochondria.
Failure of glial support, protein aggregation, inflammatory demyelin-
ation, and other mechanisms also cause axon degeneration. These may act partly
through impairment of axonal transport, and readers are referred to other recent
reviews for more details on what triggers these mechanisms (Muchowski and
Wacker, 2005; Nave and Trapp, 2008; Zhao
, 2005). This chapter aims to
move beyond observations that axonal transport is blocked in neurodegenerative
disorders by asking which cargoes are delayed, which of the resulting deficiencies
kill axons, and what determines how long this takes. Answers to these questions
are essential to move toward treating axonopathies. They are also important for
understanding the basic biology of this fascinating structure.
et al.
II. AXONAL TRANSPORT AND HOW TO BLOCK IT
A. Road closed! General defects in axonal transport
Axonal transport has to deliver proteins, vesicles, organelles, and other compo-
nents over centimeter-to-meter long distances from their sites of origin in the
cell body. This is a feat totally without comparison in any other cell type. Long-
range transport is a microtubule-based mechanism mediated in the anterograde
direction by a wide range of kinesin superfamily motor proteins and in the
retrograde direction by the dynein motor complex. For the details of the
emerging molecules and mechanisms, readers are referred to several excellent,
recent reviews (Chevalier-Larsen and Holzbaur, 2006; De Vos
et al.
, 2008;
Hirokawa and Noda, 2008; Salinas
et al.
, 2008).
