dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

Synaptic polarity depends on phosphatidylinositol signaling regulated by myo-inositol monophosphatase in Caenorhabditis elegans.

Although neurons are highly polarized, how neuronal polarity is generated remains poorly understood. An evolutionarily conserved inositol-producing enzyme myo-inositol monophosphatase (IMPase) is essential for polarized localization of synaptic molecules in Caenorhabditis elegans and can be inhibited by lithium, a drug for bipolar disorder. The synaptic defect of IMPase mutants causes defects in sensory behaviors including thermotaxis. Here we show that the abnormalities of IMPase mutants can be suppressed by mutations in two enzymes, phospholipase Cß or synaptojanin, which presumably reduce the level of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We also found that mutations in phospholipase Cß conferred resistance to lithium treatment. Our results suggest that reduction of PIP(2) on plasma membrane is a major cause of abnormal synaptic polarity in IMPase mutants and provide the first in vivo evidence that lithium impairs neuronal PIP(2) synthesis through inhibition of IMPase. We propose that the PIP(2) signaling regulated by IMPase plays a novel and fundamental role in the synaptic polarity.

Thermotaxis of C. elegans as a model for temperature perception, neural information processing and neural plasticity.

Thermotaxis is a model to elucidate how nervous systems sense and memorize environmental conditions to regulate behavioral strategies in Caenorhabditis elegans. The genetic and neural imaging analyses revealed molecular and cellular bases of this experience-dependent behavior. Surprisingly, thermosensory neurons themselves memorize the sensed temperatures. Recently developed techniques for optical manipulation of neuronal activity have facilitated the revelation that there is a sophisticated information flow between sensory neurons and interneurons. Further studies on thermotaxis will allow us to understand the fundamental logics of neural processing from sensory perceptions to behavioral outputs.

Temperature sensing by an olfactory neuron in a circuit controlling behavior of C. elegans.

Temperature is an unavoidable environmental cue that affects the metabolism and behavior of any creature on Earth, yet how animals perceive temperature is poorly understood. The nematode Caenorhabditis elegans "memorizes" temperatures, and this stored information modifies its subsequent migration along a temperature gradient. We show that the olfactory neuron designated AWC senses temperature. Calcium imaging revealed that AWC responds to temperature changes and that response thresholds differ depending on the temperature to which the animal was previously exposed. In the mutant with impaired heterotrimeric guanine nucleotide-binding protein (G protein)-mediated signaling, AWC was hyperresponsive to temperature, whereas the AIY interneuron (which is postsynaptic to AWC) was hyporesponsive to temperature. Thus, temperature sensation exhibits a robust influence on a neural circuit controlling a memory-regulated behavior.