Audhya Lab
Neurodegenerative disease
Synaptic transmission depends on the constant microtubule-based transport of organelles and vesicles to and from the distal portions of axons and dendrites. Defects in these processes can lead to a variety of neurodegenerative disorders. In particular, hereditary spastic paraplegias (HSPs) arise from a length-dependent axonopathy of corticospinal motor neurons. This diverse group of disorders is characterized by progressive lower-limb spasticity and weakness and has been linked to more than 40 unique genetic loci, many of which encode proteins that function in cytoskeleton and organelle homeostasis. However, mechanistic insights into the direct effect of mutations that cause HSPs are lacking.

In collaboration with a number of groups from around the world, we have identified and characterized the impact of a point mutation observed in two adolescent patients who exhibit a complicated form of HSP, which alters a highly conserved residue within Trk-fused gene (TFG). In addition to pronounced leg spasticity, vision problems due to optic atrophy were noted at 2.5 years of age in both children, a phenotype often linked to defects in mitochondrial function. Wasting of hand and leg muscles, as well as electromyography findings, indicated additional neuropathy, whereas there was no evidence for sensory involvement. Importantly, our previously published findings indicated that TFG functions on subdomains of the endoplasmic reticulum (ER) to regulate anterograde vesicle transport, which is mediated by COPII-coated carriers. Although COPII function has been implicated directly in dendritic growth, its potential role in axonal development and maintenance remains less clear. The single amino acid change in TFG (p.R106C) that causes HSP impairs the ability of TFG to oligomerize normally, which adversely affects its function in vivo. In non-neuronal cells, our initial studies demonstrate that inhibition of TFG results in the collapse of the ER network onto the underlying microtubule cytoskeleton, dramatically altering its morphology and dynamics. Furthermore, the distribution of mitochondria within cells lacking TFG function is highly abnormal, suggesting that TFG may function to coordinate interactions between multiple organelles and microtubules. Our goal is to explore this idea and define new mechanisms that sustain and enhance neuron viability and activity during development and aging.