CRMP2/CLN6/KLC4: Mechanisms that mediate cargo selection and transport in developing & mature axons

Batten disease is a family of devastating neurodegenerative diseases resulting from mutations in as many as 14 different genes.  Researchers have long sought a common molecular link between the various forms of Batten. Recent studies have suggested that a common Batten pathway, specifically with membrane associated protein forms of this disease (CLN3, CLN6, CLN7, CLN8), may be altered intracellular transport. We have evidence that perturbation in vesicular transport to distal neuronal sites may be a common mechanism of pathology for a subset of NCLs. Movement of cargo to distal axons and dendrites is often facilitated through the microtubule-binding protein CRMP2 and a directional kinesin motor protein. We have identified a novel complex (called the CCK complex) containing CRMP2, ER-associated CLN6, whose mutation results in CLN6-Batten disease, and kinesin light chain 4 (KLC4). CRMP2 functions to specify axon/dendrite fate and regulates cargo transport through an array of additional binding proteins. Disruption in CRMP2 function has been implicated in a host of neurological disorders, including Batten disease. Although the kinesins that CRMP2 partners with can impart some specificity for cargo selection (i.e., between different type of organelles), it remains unclear how a maturing neuron distinguishes different cargo contained in similar membrane-bound vesicles. Thus, discovery of the CCK complex reveals a novel mechanism for CLN6/CRMP2-dependent transport. The developing cerebral cortex serves as our model system and permits us to probe the CCK complex function by targeting neural progenitor cells using in utero and ex utero electroporation. We hypothesize that the CCK complex utilizes CLN6 as a “tag” on ER-vesicles to select unique cargo for transport to dendrites and/or axons. Disruption of this complex in CLN6-Batten disease would lead to insufficient support in growth and maintenance of neuronal processes and eventual degeneration. This work is being accomplished through three aims:

Aim 1: To determine how the CCK complex regulates ER-trafficking events in developing neurons

Aim 2: Define how transport via the CCK complex is linked to early events in neuronal development.

Aim 3: Determine if stabilization of CRMP2-associated complexes can ameliorate neurological deficits in a pre-clinical NCL mouse model