Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons

Abstract

Septin 5, a parkin substrate, is a vesicle-and membraneassociated protein that plays a significant role in inhibiting exocytosis. The regulatory function of Septin 5 in dopaminergic (DAergic) neurons of substantia nigra (SN), maintained at relatively low levels, has not yet been delineated. As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons. In vitro and in vivo models were used to support this hypothesis. In our wellcharacterized DAergic SN4741 cell model, acute accumulation of elevated levels of Septin 5, but not synphilin-1 (another parkin substrate), resulted in cytotoxic cell death that was markedly reduced by parkin co-transfection. A transgenic mouse model expressing a dominant negative parkin mutant accumulated moderate levels of Septin 5 in SN-DAergic neurons. These mice acquired a progressive L-DOPA responsive motor dysfunction that developed despite a 25% higher than normal level of striatal dopamine (DA) and no apparent loss of DAergic neurons. The phenotype of this animal, increased striatal dopamine and reduced motor function, was similar to that observed in parkin knockout animals, suggesting a common DAergic alteration. These data suggest that a threshold level of Septin 5 accumulation is required for DAergic cell loss and that L-DOPA-responsive motor deficits can occur even in the presence of elevated DA.

Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes

“…27,28 Interestingly, a neuron defect has been difficult to document in septin-5 Ϫ/Ϫ mice, but platelets lacking the protein demonstrate enhanced aggregation and release stored granule products in response to stimuli that are under the threshold for normal platelets. 15 Septin-5 has been localized to membrane areas surrounding platelet ␣-granules and binds syntaxin 4 to prevent rather than promote secretion.…”

Septin Expression in Proliferative Retinal Membranes

“…In addition, septin-dependent recruitment of a class of kinases to the bud neck region is a checkpoint for cell cycle progression. It has been demonstrated that septins can produce neuronal toxicity and motor behavioral dysfunction in dopaminergic neurons (Son et al 2005). They may also contribute to neoplasia by enhancing membrane dynamics (Polo et al 2004).…”

MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression

“…Isolated midbrain sections (dissected as described in the study by Son and colleagues 26 ) were transferred to ice-cold Hank's Balanced Salt Solution (HBSS; Life Technologies), supplemented with 500 units of penicillin and 500 µg of streptomycin directly after isolation. Midbrains were then washed twice with 12 mL of HBSS and trypsinized in 4 mL of HBSS with 0.5% trypsin.…”