Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling

Binding of target-derived neurotrophins to Trk receptors at nerve terminals are required to stimulate neuronal survival, differentiation, innervation and synaptic plasticity. The distance between the soma and nerve terminal is tremendous, making efficient anterograde Trk transport critical for their synaptic translocation and signaling. The mechanism responsible for this trafficking remains poorly understood. Here we show that the sorting receptor sortilin interacts with TrkA, -B, and –C and enables their anterograde axonal transport, thereby enhancing neurotrophin signaling. Cultured DRG neurons lacking sortilin exhibit blunted MAPK signaling and reduced neurite outgrowth upon stimulation with NGF. Moreover, deficiency for sortilin considerably aggravates TrkA, -B- and –C phenotypes present in p75(NTR) knockouts, and results in increased embryonic lethality and sympathetic neuropathy in mice heterozygous for TrkA. Our findings demonstrate a novel and unexpected role for sortilin as an anterograde trafficking receptor for Trk and a positive modulator of neurotrophin-induced neuronal survival

The Pak1 kinase : an important regulator of neuronal morphology and function in the developing forebrain

The mammalian central nervous system (CNS) represents a highly complex unit, the correct function of which relies on the appropriate differentiation and survival of its neurones. It is becoming apparent that the Rho family of small GTPases and their downstream targets have a major function in regulating CNS development. Among the effectors, the role of the Pak family of kinases, especially Pak1, is becoming increasingly evident. Although highest levels of Pak1 expression and activation are detected in the developing nervous system, much remains undiscovered concerning its function in neurones. This review summarises what is currently known regarding the biological and molecular role of Pak1 in the mammalian forebrain. It emphasises the importance of Pak1 in regulating neuronal polarity, morphology, migration and synaptic function. Consequently, there are also strong indications that Pak1 is required for normal cognitive function. Furthermore, loss of Pak1 has been associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease, while up-regulation and de-regulation may be responsible for oncogenic transformation of support cells within the CNS, especially astrocyte progenitors. Together, these new and exciting findings encourage the future exploration into the function of Pak1 in the nervous system, thus, paving the way for novel strategies towards improved diagnosis and therapeutic treatment of diseases that affect the CNS.Peer reviewe