Biology subjects

Mushtaq, Z.

Publications and source records attributed to Mushtaq, Z..

5 recordsLinked to original sources

bioRxiv2026

Loss of NudE-mediated dynein activation at synaptic terminals causes progressive axon length-dependent neurodegeneration

Progressive, axon length-dependent degeneration of nerve terminals is a defining feature of dying-back neuropathies; yet, whether defects in axonal transport initiate or are a consequence of this process remains unresolved. Here, we show that NudE, a scaffold for dynein motor activation, is required for the initiation of retrograde axonal transport at Drosophila motoneuron synapses in vivo. Loss of NudE impairs dynein activation at the synaptic terminal, severely reducing the proportion of cargo entering retrograde transport and decreasing retrograde motor velocity. Live imaging and temporal analysis establish that this transport initiation defect is the earliest event in a degenerative cascade, followed by progressive microtubule destabilization, impaired synaptic transmission, and structural degeneration in a distal-to-proximal gradient that recapitulates dying-back neuropathies. Structure-function analysis validates the biochemically defined NudE-dynein binding domains in vivo, with graded disruption producing correspondingly graded phenotypes. Genetic two-hit experiments uncover a reciprocal dependence between transport initiation and microtubule maintenance: perturbations in either process that are individually tolerated synergistically trigger degeneration when combined, while increasing microtubule levels alone cannot compensate for failed dynein activation. These findings reveal retrograde transport initiation as a critical vulnerability point in motoneurons and provide a mechanistic basis for how defects in dynein activation produce progressive neurodegeneration.

neuroscience↗

bioRxiv2024

Endocytosis restricts synapse growth by attenuating Highwire/PHR1-dependent JNK signaling in a pathway parallel to the BMP signaling

Synaptic growth and organization are orchestrated by pre - and post-synaptic signaling, neuronal activity, and environmental cues. Although endocytosis is known to attenuate synaptic growth, the underlying signaling mechanisms have remained elusive. Here, we uncover a previously unrecognized mechanism by which endocytosis constrains synaptic growth through regulation of the neuronal E3 ubiquitin ligase Highwire (Hiw/Phr1). We show that loss of endocytosis causes Hiw to accumulate in neuronal cell bodies, leading to elevated MAP3K Wallenda (Wnd)/DLK levels and hyperactivation of JNK signaling. The accumulated Hiw assembles into dynamic liquid-liquid phase-separated condensates, as revealed by their rapid and reversible dissolution with 1,6-hexanediol. Acute blockade of endocytosis using a temperature-sensitive dynamin mutant Shibiretssimilarly triggered robust Hiw phase separation. We further demonstrate that Rab11-positive recycling endosomes are essential for proper Hiw localization and turnover, directly linking endosomal trafficking to the control of JNK signaling. Finally, we show that both BMP and JNK signaling are necessary and sufficient to guide synaptic morphogenesis at the Drosophila NMJ, thereby integrating endocytic trafficking with synaptic growth signaling. Our findings establish endocytosis as a critical regulator of Hiw/Phr1-dependent JNK signaling via liquid-liquid phase separation, with implications that extend beyond synaptic morphogenesis to axon injury and degeneration pathways.

neuroscience↗

bioRxiv2024

Drosophila Asap regulates cellular protrusions via dArf6-dependent actin regulatory pathway

Membrane protrusions are fundamental to cellular functions like migration, adhesion, and communication and depend upon the dynamic reorganization of the cytoskeleton. The GAP-dependent GTP hydrolysis of Arf proteins regulates actin-dependent membrane remodeling. Here, we show that the dAsap regulates membrane protrusions in S2R+ cells by a mechanism that critically relies on its ArfGAP domain and re-localization of actin regulators, SCAR, and Ena. While our data reinforce the preference of dAsap for Arf1 GTP hydrolysis in vitro, we demonstrate that induction of membrane protrusions in S2R+ cells depends on Arf6 inactivation. This study furthers our understanding of how dAsap-dependent GTP hydrolysis maintains a balance between active and inactive states of dArf6 to regulate cell shape.

cell biology↗

bioRxiv2020

Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disease manifesting in the premutation (PM) carriers of the FMR1 gene with alleles bearing 55-200 CGG repeats. The discovery of a broad spectrum of clinical and cell developmental abnormalities among PM carriers with or without FXTAS, and in model systems suggests that neurodegeneration seen in FXTAS could be the inevitable end-result of pathophysiological processes set during early development. Hence, it is imperative to trace early pathological abnormalities. Our previous studies have shown that transgenic Drosophila carrying human-derived fragile X premutation-length CGG repeats are sufficient to cause neurodegeneration. Here, we used the same transgenic Drosophila model to understand the effects of fragile X premutation-length CGG repeats on the structure and function of the developing nervous system. We show that presynaptic expression of the premutation length CGG repeats restricts synaptic growth, reduces the number of synaptic boutons, leads to aberrant presynaptic varicosities, and impairs synaptic transmission at the larval neuromuscular junctions (NMJs). The postsynaptic analysis shows both glutamate receptor and subsynaptic reticulum proteins are normal. However, a high percentage of boutons show the reduced density of Bruchpilot protein, a key component of presynaptic active zones required for vesicle release. The electrophysiological analysis shows a significant reduction in the quantal content, a measure of total synaptic vesicles released per excitation potential. Together these findings endorse that synapse perturbation caused by rCGG repeats mediate presynaptically during larval NMJ development.

pathology↗

bioRxiv2020

Dmon1 and rab7 interact to regulate glutamate receptor GluRIIA levels at the larval Drosophila neuromuscular junction.

Regulation of post-synaptic receptors plays an important role in determining synaptic strength and plasticity. The Drosophila larval neuromuscular junction (nmj) has been used extensively as a model to understand some of these processes. In this context, we are interested in the role of Drosophila Monensin sensitive protein 1 (DMon1) in regulating glutamate receptor (GluRIIA) levels at the nmj. Dmon1 is an evolutionarily conserved protein which, in complex with CCZ1, regulates the conversion of early endosomes to late endosomes through recruitment of Rab7. C-terminal deletion mutants of Dmon1 (Dmon1{Delta}181) exhibit lethality. The escapers have a short life span and exhibit severe motor defects. At the nmj, these mutants show a defects in synaptic morphology and a strong increase in glutamate receptor GluRIIA levels. The mechanism by which Dmon1 regulates GluRIIA is unclear. In this study, we have described the characterization the mutation in an EMS mutant referred to as pog1 and demonstrate this mutant to be an allele of Dmon1. Further, we have examined the role of rab7 in regulation the of GluRIIA. We show that similar to Dmon1, knock-down of rab7 using RNAi in neurons, and not muscles, leads to an increase in GluRIIA. Loss of one copy each of Dmon1 with rab7 leads to a synergistic increase in receptor expression. Further, overexpression of an activated Rab7 can rescue the GluRIIA phenotype observed in Dmon1{Delta}181 mutants. Together, these results highlight a neuronal role for Rab7 in GluRIIA regulation and underscores the important of the endo-lysosomal pathway in this process.

genetics↗