Using screening approaches in primary neurons, we previously identified BDNF as a major inducer of Sorl1
that activates receptor gene transcription through the ERK pathway. Induction of Sorl1
transcription results in a robust increase in SORLA protein expression and activity in cultured neurons and in the mouse brain in vivo
. A clue towards understanding the physiological relevance of SORLA as downstream target of BDNF signaling came with the proteomics analyses in this study that documented a blunted response of SORLA-deficient neurons to BDNF application ( and ). The underlying molecular mechanism was revealed in studies in cultured neurons demonstrating a hitherto unknown function for SORLA in axonal trafficking of TrkB, a step critical for efficient neurotrophin signal transduction ( and ).
To elicit its biological effects, BDNF signals must be conveyed over long distances from the nerve terminal to the cell body 
. In detail, nascent TrkB receptor molecules are targeted anterogradely along the axonal path to the synapse. Following neurotrophin binding to Trk receptors, receptor-ligand complexes internalize in signaling endosomes and signaling persists within these vesicles as they move retrogradely back to the cell body to control gene expression 
. The detailed mechanisms of TrkB transport are not fully resolved. Conceptually, our studies support a model whereby physical interaction with SORLA facilitates neuritic transport of TrkB to and from the synapse, promoting BDNF signal transduction from nerve termini to cell soma. Lack of SORLA, as in primary Sorl1−/−
neurons, results in enhanced accumulation of TrkB at the synaptic plasma membrane and in depletion from the post-synaptic density compartment (). Also, anterograde as well as retrograde transport of TrkB along neurites is delayed in the absence of the receptor (). Several cytosolic adaptor proteins, including GGA (Golgi-localized, gamma adaptin ear-containing, ARF-binding protein), phosphofurin acidic cluster sorting protein 1, and retromer have been shown to interact with the carboxy-terminal tail of SORLA and to direct its intracellular trafficking path 
. Potentially, these interactions not only govern SORLA-dependent transport of APP but of TrkB as well. Clearly, the molecular mechanisms controling SORLA-dependent antero/retrograde sorting of TrkB at the synapse and its relevance for promotion of signal transduction still await elucidation.
A similar function as for SORLA in trafficking of TrkB has been documented for sortilin, a related receptor,of the VPS10P domain receptor family 
. Unlike sortilin, that mainly regulates anterograde transport of TrkB, SORLA apparently controls both, anterograde and retrograde sorting of this receptor. In addition, Sorl1
but not the gene encoding sortilin is induced by BDNF in neurons 
. Thus, SORLA appears as integral part of a self-potentiating activation loop whereby BDNF distinctly induces SORLA expression to accelerate axonal transport of its cognate receptor and to strengthen trophic signals. Further support for the specificity of this activation loop stems from the fact that BDNF but not other neurotrophins (such as NGF) induced Sorl1
BDNF signaling has long been recognized as an autocrine mechanism whereby adult sensory neurons secrete BDNF to sustain their own survival signals 
. A more complicated scenario is true in the striatum where BDNF produced in cortical neurons needs to be transported to striatal neurons to support their survival. Striatal neuronal cell loss due to insufficient BDNF support has been recognized as a molecular mechanism in HD, a monogenic disease caused by a polyglutamine expansion (polyQ) in huntingtin. Huntingtin is a protein that facilitates vesicular transport of BDNF along microtubules. Compared to the wild-type protein, the polyQ-mutated huntingtin fails to efficiently transport BDNF, resulting in loss of trophic support and in neuronal toxicity 
. Experimental evidence suggests that BDNF arrives in the striatum by anterograde transport from the cortex via cortico-striatal afferents 
. We have reported before that in Huntington diseased mice (HD82) low levels of striatal BDNF result in low levels of SORLA 
. Now, we show that complete loss of SORLA expression in HD82 mice aggravates the neuromotoric decline in this model of HD (). These findings further support the pathophysiological relevance of impaired BDNF trophic support in HD, and the relevance of SORLA as neuronal sorting receptor for TrkB in the molecular pathogenesis of this disease.