The cytoskeleton protein α-fodrin plays a major role in maintaining structural stability of membranes. It was also identified as part of the brain γ-tubulin ring complex, the major microtubule nucleator. Here, we investigated the requirement of α-fodrin for microtubule spindle assembly during mitotic progression. We found that α-fodrin depletion results in abnormal mitosis with uncongressed chromosomes, leading to prolonged activation of the spindle assembly checkpoint and a severe mitotic delay. Further, α-fodrin repression led to the formation of shortened spindles with unstable kinetochore-microtubule attachments. We also found that the mitotic kinesin CENP-E had reduced levels at kinetochores to likely account for the chromosome misalignment defects in α-fodrin-depleted cells. Importantly, we showed these cells to exhibit reduced levels of detyrosinated α-tubulin, which primarily drives CENP-E localization. Since proper microtubule dynamics and chromosome alignment are required for completion of normal mitosis, this study reveals an unforeseen role of α-fodrin in regulating mitotic progression. Future studies on these lines of observations should reveal important mechanistic insight for fodrin's involvement in cancer.

Significance The accumulation of nonfunctional α-synuclein (α-syn FL ) oligomers is the hallmark of Parkinson’s disease (PD), affecting millions of people worldwide. Although α-syn FL has a central role in PD, its cellular function is unclear until now. Understanding the normal function of α-syn FL is critical to envisage the molecular basis of abnormal cellular secretion under disease conditions. Previous studies indicated that it can regulate various steps of membrane fusion. Fusion pores are the crucial kinetic intermediates during membrane fusion, through which vesicular secretion occurs from different cell types. Here, we describe a function of α-syn FL in regulating the microsecond fusion pore transitions. This study offers an insight into how abnormal secretion occurs under pathological conditions in which nonfunctional α-syn FL accumulates.

Non‐erythroid spectrin or fodrin is present as part of the γ‐tubulin ring complex (γ‐TuRC) in brain tissue and brain derived cells. Here, we show that fodrin, which is otherwise known for providing structural support to the cell membrane, interacts directly with γ‐tubulin within the γ‐TuRC through a GRIP2‐like motif. Turbidometric analysis of microtubule polymerization with nucleation‐potent γ‐TuRC isolated from HEK‐293 cells that lack fodrin and the γ‐TuRC from goat brain that contains fodrin shows inefficiency of the latter to promote nucleation. The involvement of fodrin was confirmed by the reduction in the microtubule polymerization efficiency of HEK‐293 derived γ‐TuRCs upon addition of purified brain fodrin. Thus, the interaction of fodrin with gamma‐tubulin is responsible for its inhibitory effect on γ‐tubulin mediated microtubule nucleation.

Fodrin and its erythroid-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in mammalian cells, which is necessary for proper cell function. Normal cell morphology is altered in diseases, like various cancers and certain neuronal disorders. Fodrin and spectrin are two-chain (αβ) molecules that are encoded by paralogous genes and share many common features, but also demonstrate certain differences. Fodrin (in humans, typically, a heterodimer of the products of the SPTAN1 and SPTBN1 genes) is expressed in nearly all cell types, and is especially abundant in neuronal tissues, whereas spectrin (in humans, a heterodimer of the products of the SPTA1 and SPTB1 genes) is expressed almost exclusively in erythrocytes. To fulfill a role in such a variety of different cell types, it was anticipated that fodrin would need to be a more versatile scaffold than spectrin. Indeed, as summarized here, domains unique to fodrin and its regulation by Ca2+, calmoduln, and a variety of post-translational modifications (PTMs) endow fodrin with additional specific functions. However, how fodrin structural variations and misregulated PTMs may contribute to the etiology of various cancers and neurodegenerative diseases needs to be further investigated.