Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila

Abstract

Tauopathies, including Alzheimer's disease and fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of aberrantly phosphorylated-tau. Tau is a neuronal microtubule-associated protein involved in microtubule assembly and stabilization. Currently, the molecular mechanisms underlying tau-mediated cellular toxicity remain elusive. To address the determinants of tau neurotoxicity, we first characterized the cellular alterations resulting from the over-expression of a mutant form of human tau associated with FTDP-17 (tau V337M) in Drosophila. We found that the over-expression of tau V337M, in Drosophila larval motor neurons, induced disruption of the microtubular network at presynaptic nerve terminals and changes in neuromuscular junctions morphological features. Secondly, we performed a misexpression screen to identify genetic modifiers of the tau V337M-mediated rough eye phenotype. The screening of 1250 mutant Drosophila lines allowed us to identify several components of the cytoskeleton, and particularly from the actin network, as specific modifiers of tau V337M-induced neurodegeneration. Furthermore, we found that numerous tau modulators identified in our screen were involved in the maintenance of synaptic function. Taken together, these findings suggest that disruption of the microtubule network in presynaptic nerve terminals could constitute early events in the pathological process leading to synaptic dysfunction in tau V337M pathology.

LRRK2G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β

“…Our results suggest a genetic correlation between G2019S and tau in microtubule fragmentation and inclusion formation, two pathogenic processes involving tau hyperphosphorylation (Blard et al, 2007). It is therefore important to examine whether G2019S affects the phosphorylation status of tau.…”

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

“…From these studies, multiple kinases, phosphatases, and cytoskeletal proteins have been shown to modulate tau neurotoxicity (20,29,30). MT defects, a hallmark of tauopathies, contribute directly to neurodegeneration (31)(32)(33).…”

“…MTs play a critical role in the development of Drosophila larval NMJ synapses (12,13,18,19). Previous studies demonstrated that overexpression of human tau in Drosophila motor neurons results in abnormal NMJ morphology (20,21). Consistent with these observations, we found that there were significantly more satellite boutons-defined as small boutons that bud from major synaptic terminals or primary boutons-at the NMJ terminals of larvae overexpressing tau V337M (11.5 ± 1.4) or tau WT (9.6 ± 1.1) driven by elav-Gal4 compared with the genetic controls (4.1 ± 0.5) (Fig.…”

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…In general, non-MT-associated tau functions can be characterized as involving an alternative association of either MTBR region [94,121,122] or N-terminal domains of tau with subcortical actin [75], actin-associated proteins such as dynactin [123][124][125] and membrane associated proteins involved in signal transduction such as fyn and src [126]. Additional non-…”