Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity

Abstract

In Parkinson disease (PD), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

Septin 11 Is Present in GABAergic Synapses and Plays a Functional Role in the Cytoarchitecture of Neurons and GABAergic Synaptic Connectivity

“…It has been reported that a septin 4 null mouse has a phenotype, including male infertility and anatomical abnormalities of the cerebellum (13,66). However, the knock-out septin 3, septin 5, or septin 6 mice showed no apparent effect on brain phenotype (7,66,67), indicating that there is developmental compensation and/or functional redundancy of various septins.…”

“…The mouse anti-septin 7 ascites fluid was a gift from Dr. Randall Walikonis (University of Connecticut) (20). The guinea pig anti-rat ␥2 (to amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] antibody was raised in our laboratory and affinity-purified on immobilized peptide. The specificity of the guinea pig anti-rat ␥2 antibody has been determined previously (21)(22)(23)(24)(25)(26)(27)(28).…”

Septin 8 is an interaction partner and in vitro substrate of MK5

“…-/-mice had defects in behavior and reproduction, while SEPT5 -/-animals had elevated platelet hypersensitivity [25][26][27] . Septins have been reported to be perturbed in various human diseases, including neurological disorders, infection, and neoplasia [28] .…”

Etiology and Pathogenesis of Parkinson’s Disease

“…Electrophysiological study in -synuclein knockout mice revealed that -synuclein could act as an activitynegative regulator of DA neurotransmission at synaptic terminals (Abeliovich et al 2000). -synuclein is also speculated to have various other functions, such as modulation of tyrosine hydroxylase (TH) activation (Perez et al 2002), inhibition of vesicular monoamine transporter-2 (VMAT2) activity , and interaction with septin4, which have been implicated in exocytosis (Ihara et al 2007). Recently, Cooper and colleagues reported that -synuclein blocked endoplasmic reticulum (ER)-to-Golgi vesicular trafficking, and induced ER stress followed by cell death (Cooper et al 2006).…”