Abstract:

The membrane trafficking system plays an important role in the nervous system. Some membrane proteins are removed from the plasma membrane by incorporation into endocytic structures, which become early endosomes. Next, these proteins are sorted into the luminal space by invagination of the endosomal limiting membrane, leading to the formation of multivesicular bodies (MVBs). MVBs are morphologically distinct from late endosomes that internally accumulate small membrane vesicles containing the cargo proteins. The formation of MVBs is catalyzed by the Endosomal sorting complex required for transport (ESCRT) complexes, ESCRT-I, ESCRT-II, and ESCRT-III. These complexes form a network that recruits mono-ubiquitinated proteins and drives their internalization into luminal vesicles of MVBs. Finally the fusion of MVBs with lysosomes delivers internal vesicles and cargo proteins into the lysosomal lumen, where they are degraded by lysosomal proteases and lipases. Since the membrane trafficking system is essential for the regulation of morphology, development, and survival of neurons, studies in this field give useful insights that contribute to our understanding of the brain. Recently, we have reported a novel mechanism that underlie PtdIns(3,5)P2 functions in neurons. Previously, we reported that PIKfyve-produced PtdIns(3,5)P2 play important roles in the protection of excitotoxic cell death via regulation of voltage-gated calcium channel, CaV1.2 expression. In neurons, intracellular Ca2+ concentration is an important factor to coordinate neuronal activity. Indeed, our studies have shown that bath glutamate application promotes the internalization of CaV1.2 from the plasma membrane, leading to lysosomal degradation. As many neurodegenerative disorders are implicated in both membrane trafficking and Ca2+ homeostasis, the mechanisms identified in our study may provide an important clue of why perturbed PtdIns(3,5)P2 metabolism causes neurodegeneration such as ALS and Charcot-Marie-Tooth disease.
In conclusion, our recent study has reported that PIKfyve mediates endolysosomal motility in neurons. PtdIns(3,5)P2 play important roles in a variety of cellular functions. It is also known that dysregulation of PtdIns(3,5)P2 metabolism causes neuromuscular disorders such as Charcot-Marie-Tooth disease and ALS. Thus, our finding shed light on a novel function of PtdIns(3,5)P2 and provide an important clue that links perturbed PtdIns(3,5)P2 metabolism to neurodegenerative disorders.