Biology subjects

Lins, J.

Publications and source records attributed to Lins, J..

2 recordsLinked to original sources

bioRxiv2020

Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning & reduces neurodegeneration

mRNA transport in neurons is a ubiquitous process but has been often overlooked as a contributor to disease. Mutations of transport granule protein hnRNPA2 cause hereditary proteinopathy of neurons, myocytes, and bone. Here, we examine transport granule component specificity, assembly/disassembly, and the link to neurodegeneration. hnRNPA2 transport granule components hnRNPF and ch-TOG interact weakly with hnRNPA2 yet they each partition specifically into hnRNPA2 liquid phases. hnRNPA2 tyrosine phosphorylation dissociates granule interactions by reducing hnRNPA2 phase separation and preventing partitioning of hnRNPF and ch-TOG; tyrosine phosphorylation also decreases aggregation of hnRNPA2 disease mutants. A C. elegans model of hnRNPA2 D290V-associated neurodegeneration exhibits TDP-43 ortholog-dependent glutamatergic neurodegeneration. Expression of the tyrosine kinase that phosphorylates hnRNPA2 reduces glutamatergic neurodegeneration. The evidence for specific partitioning of granule components as well as disruption of these interactions and reduction of neurodegeneration by tyrosine phosphorylation suggest transport granule biology has a role in the pathogenesis of neurodegeneration.

biochemistry↗

bioRxiv2019

Disrupted Autophagy and Neuronal Dysfunction in C. elegans Knockin Models of FUS Amyotrophic Lateral Sclerosis

It remains unclear how mutations in FUS, a ribonucleoprotein, lead to neuronal dysfunction in Amyotrophic Lateral Sclerosis (ALS) patients. To examine mechanisms underlying ALS FUS dysfunction, we generated the first C. elegans knock-in models using CRISPR/Cas9-mediated genome editing, creating R524S and P525L ALS FUS models. Although FUS inclusions were not detected, ALS FUS animals showed defective neuromuscular function, as well as stress-induced locomotion defects. Unlike C. elegans lacking the endogenous FUS ortholog, ALS FUS animals had impaired neuronal autophagy and increased SQST-1 accumulation in ALS FUS motor neurons. Loss of sqst-1, the C. elegans ortholog for ALS-linked, autophagy adaptor protein SQSTM1/p62, suppressed both neuromuscular and stress-induced locomotion defects in ALS FUS animals, but did not suppress neuronal autophagy defects. Therefore, autophagy dysfunction is upstream of, and not dependent on, SQSTM1 function in ALS FUS pathogenesis. Combined, our findings demonstrate that autophagy dysfunction likely contributes to protein homeostasis and neuromuscular defects in ALS FUS knock-in animals.

neuroscience↗